CN103703005A - Tricyclic inhibitors of kinases - Google Patents

Tricyclic inhibitors of kinases Download PDF

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CN103703005A
CN103703005A CN201280018862.6A CN201280018862A CN103703005A CN 103703005 A CN103703005 A CN 103703005A CN 201280018862 A CN201280018862 A CN 201280018862A CN 103703005 A CN103703005 A CN 103703005A
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phenyl
amino
pyrimidine
imidazo
kui linpyrimido
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童云松
T.D.彭宁
A.弗洛尔詹奇克
J.米亚施罗
K.W.伍兹
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AbbVie Inc
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
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    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract

The invention relates to compounds of formula (I) or pharmaceutical acceptable salts, (l) wherein X, Y, Z, R<3> and R<4> are defined in the description. The present invention relates also to compositions containing the compounds which are useful for inhibiting kinases such as wee-1 and methods of treating diseases such as cancer.

Description

Kinase whose tricyclic inhibitors
Invention field
The present invention relates to suppress the compound of Wee-1 kinase activity, the method for preparing this compound, the composition that contains this compound and use the methods for the treatment of of this compound.
background of invention
In order to carry out correct cell fission, eukaryotic cell must copy their genome faithfully, then their karyomit(e) is accurately separated in two daughter cells.This fissional process, is also called the cell cycle, is the step-by-step procedure that depends on check point, thereby guarantees genomic integrity.Once DNA replication dna complete (S phase), cell enters vegetative period (G2 phase), then carries out the mitotic division (M-phase) of chromosome segregation.Mitotic crucial conditioning agent be kinase c dk1 (being called Cdc2) (Nurse, P. (1990) Universal control mechanism regulating onset of M-phase. Nature 344,503-508).The activation of Cdk1, causes mitotic initially, and its inactivation subsequently causes and exits mitotic division.Cdk1 is by being activated in conjunction with cyclin A or cell periodic protein B.Cyclin A-Cdk1 and cell periodic protein B-Cdk1 mixture can cause mitotic division (Lindqvist, A., Deng people (2009). The decision to enter mitosis:feedback and redundancy in the mitotic entry network. The Journal of cell biology 185,193-202).The degraded of Cyclin B causes the inactivation of Cdk1, cause mitotic division to stop, and enter into growth (G1) phase, then start the cell cycle (Glotzer of a new round, M., Deng people (1991) Cyclin is degraded by the ubiquitin pathway. Nature 349,132-138).
Except cyclin; Wee1 also regulates Cdk1; it is the Cdk1 on phosphorylated tyrosine 15 (Y15) the atypical Tyrosylprotein kinase (McGowan that makes Cdk1 inactivation; C.H.; Deng people (1993) Human Wee1 kinase inhibits cell division by phosphorylating p34cdc2 exclusively on Tyr15. The EMBO journal 12,75-85; Parker, L.L., waits people (1992) Inactivation of the p34cdc2-cyclin B complex by the human WEE1 tyrosine kinase. Science 257,1955-1957).Wee1 is the crucial negative regulator agent of Cdk1, and work at G2-M phase check point, guarantee that DNA replication dna completes, and guaranteed before entering mitotic division not lesioned gene group (people (1997) the Chk1 is a wee1 kinase in the G2 DNA damage checkpoint inhibiting cdc2 by Y15 phosphorylation. The EMBO journal 16 such as O'Connell, 545-554).The forfeiture of Wee1 can cause entering too early mitotic division, cause mitotic division failure and necrocytosis (Stumpff, J., Deng people (2004) Drosophila Wee1 kinase regulates Cdk1 and mitotic entry during embryogenesis. Curr Biol 14,2143-2148).In addition, the G1 phase check point of many cancers is defective, and depend on G2-M phase check point (Sancar, A., Deng people (2004) Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Annual review of biochemistry 73,39-85).In fact, show, disappearance due to p53 albumen, losing Wee1 expresses and will cause the cancellation of G2-M phase check point, and make tumour cell to DNA damage sensitization, especially lost those tumours (Wang of G1 phase check point, Y., Deng people (2004) Knockdown of Chk1, Wee1 and Myt1 by RNA interference abrogates G2 checkpoint and induces apoptosis. Cancer biology & therapy 3,305-313).
The inhibitor of Wee1 has the potentiality that selectivity is impelled the defective cancer cell death of other Cell cycle checkpoint, meanwhile, does not damage the healthy tissues that can activate other Cell cycle checkpoint.Therefore, the micromolecular inhibitor of Wee1 is of value to the Results of cancer and other cell proliferation illness.
the present invention's general introduction
The present invention has many embodiments.Therefore, one embodiment of the invention relate to the have formula compound of (I)
Figure 2012800188626100002DEST_PATH_IMAGE001
Wherein X, Y, Z, R 3, R 4as defined with its lower hyte below.
Also provide pharmaceutically acceptable composition, the array configuration that it comprises formula (I) compound and pharmacologically acceptable salt and the pharmacy suitable carrier for the treatment of significant quantity.
An embodiment relates to the method for the treatment of mammiferous cancer, and the method comprises: the compound or pharmaceutically acceptable salt thereof that gives the formula (I) of its treatment acceptable amount.Another embodiment relates to the method that reduces mammiferous gross tumor volume, and the method comprises: the compound or pharmaceutically acceptable salt thereof that gives the formula (I) of its treatment acceptable amount.
detailed description of the present invention
The target of this detailed description just makes others skilled in the art be familiar with applicant's invention, its principle and its practical application, make others skilled in the art revise and to use the present invention by many forms, make them can be very suitable for the concrete requirement of using.The object of this specification sheets and its specific embodiment just illustrates.Therefore, the present invention is not limited to the described embodiment of this patent application, and can carry out various improvement.
abbreviation and definition
Unless definition in addition herein, otherwise the Science and Technology term being combined with the present invention has the implication that those of ordinary skills understand conventionally.The implication of term and scope should be clear, yet if there is any potential ambiguity, definition provided herein has precedence over any dictionary or external definition.In this application, the purposes of "or" refers to "and/or", except as otherwise noted.In addition, term " comprises (including) " (and other form, for example, " comprise (includes) " and " comprising (included) ") does not have restricted.The word using about present patent application (comprising claim) " comprises (comprise) " or " comprising (comprises) " or " containing (comprising) ", applicant points out: unless the context requires otherwise, otherwise, should be based on being interpreted as with clear: using those words is inclusives, rather than exclusive, and applicant wishes so to explain each word in those words in the process of explaining present patent application (comprising following claim).For occurring once above variable at any substituting group or in compound of the present invention or any other formula herein, definition when its definition when at every turn occurring and other occur has nothing to do.Substituting group can combine, but requires this combination results stable compound.Stable compound be can be from reaction mixture with the compound of useful purity separation.
Should be appreciated that, be all combinations herein, maintain suitable atoms valency, and the unit price with an above atom partly connects by their left end, draws from left to right divalent moiety.
The following term of using in this specification sheets and accessory claim has the implication indicating, unless illustrated unlike this:
Term " alkyl " (combining separately or with other term) refers to straight or branched saturated hydrocarbyl substituting group, typically contains 1 to about 10 carbon atoms; Or in another embodiment, contain 1 to about 8 carbon atoms; In another embodiment, contain 1 to about 6 carbon atoms; In another embodiment, contain 1 to about 4 carbon atoms.This substituent example comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl and hexyl etc.
Term " thiazolinyl " (combining separately or with other term) refers to the straight or branched hydrocarbyl substituent that contains one or more pairs of keys, typically contains 2 to about 10 carbon atoms; Or in another embodiment, contain 2 to about 8 carbon atoms; In another embodiment, contain 2 to about 6 carbon atoms; In another embodiment, contain 2 to about 4 carbon atoms.This substituent example comprises vinyl, 2-propenyl, 3-propenyl, Isosorbide-5-Nitrae-pentadienyl, Isosorbide-5-Nitrae-butadienyl, 1-butylene base, crotyl and 3-butenyl etc.
Term " alkynyl " (combining separately or with other term) refers to the straight or branched hydrocarbyl substituent that contains one or more triple bonds, typically contains 2 to about 10 carbon atoms; Or in another embodiment, contain 2 to about 8 carbon atoms; In another embodiment, contain 2 to about 6 carbon atoms; In another embodiment, contain 2 to about 4 carbon atoms.This substituent example comprises ethynyl, 2-propynyl, 3-proyl, 2-butyne base and 3-butynyl etc.
Term " carbocylic radical " (separately or with other term combination) refer to contain 3 to 14 carboatomic ring atoms (" annular atoms " is the atom that is combined together to form the ring of ring substituents) saturated rings (, " cycloalkyl "), fractional saturation ring (, " cycloalkenyl group ") or the hydrocarbyl substituent of completely unsaturated (that is, " aryl ").Carbocylic radical can be monocycle or polynuclear plane.
Carbocylic radical can be single ring architecture, and it typically contains 3 to 8 annular atomses, more typically contains 3 to 6 annular atomses, and even more typically contains 5 to 6 annular atomses.The example of this monocycle carbocylic radical comprises cyclopropyl (cyclopropane base), cyclobutyl (tetramethylene base), cyclopentyl (pentamethylene base), cyclopentenyl, cyclopentadienyl, cyclohexyl (cyclohexyl), cyclohexenyl, cyclohexadienyl and phenyl.Carbocylic radical can be also many ring carbocylic radicals (that is, can contain more than one ring).The example of many ring carbocylic radicals comprises bridging, condenses and volution carbocylic radical.In volution carbocylic radical, two different rings have an atom.The example of volution carbocylic radical is spiropentane base.In the carbocylic radical of bridging, ring is shared at least two shared non-conterminous atoms.The example of bridging carbocylic radical comprises two rings [2.2.1] heptyl, two ring [2.2.1] hept-2-ene" base and adamantyls.In the ring carbocylic radical system condensing, two or more rings can condense together, make two rings share a common key.The example of two or three condensed ring carbocylic radicals comprises naphthyl, tetralyl, indenyl, indanyl (dihydro indenyl), anthryl, phenanthryl and naphthalane base.
Term " cycloalkyl " (combining separately or with other term) refers to the saturated cyclic hydrocarbon group substituting group that contains 3 to 14 carboatomic ring atoms.Cycloalkyl can be monocyclic carbocyclic ring, and it typically contains 3 to 8 carboatomic ring atoms, and more typically contains 3 to 6 annular atomses.The example of monocyclic cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.Cycloalkyl can be also polycyclic naphthene base or contain the cycloalkyl that surpasses a ring.The example of polycyclic naphthene base comprises bridging, condenses and volution carbocylic radical.
Term " aryl " (combining separately or with other term) refers to the aromatic carbon cyclic group that contains 6 to 14 carboatomic ring atoms.Aryl can be monocycle or polyaromatic (that is, can contain more than one ring).The in the situation that of many ring aromatic nucleus, only require that in multi-loop system, having a ring is unsaturated ring, and remaining ring can be saturated, fractional saturation or unsaturated ring.The example of aryl comprises phenyl, naphthyl, indenyl, indanyl and tetralyl.
In some cases, for example, carbonatoms in hydrocarbyl substituent (, alkyl, thiazolinyl, alkynyl or cycloalkyl) is by prefix " C x-C y-" represent, wherein x is minimum carbonatoms in substituting group, y is maximum carbonatoms in substituting group.Thus, for example, " C 1-C 6-alkyl " refer to the alkyl substituent that contains 1 to 6 carbon atom.Further illustrate C 3-C 8cycloalkyl refers to the stable hydrocarbon basic ring that contains 3 to 8 carboatomic ring atoms.
Term " hydrogen " (combining separately or with other term) refers to hydrogen atom group and can be write as-H.
Term " hydroxyl " (combining separately or with other term) refers to-OH.
Term " carboxyl " (combining separately or with other term) refers to-C (O)-OH.
Term " amino " (combining separately or with other term) refers to-NH 2.
Term " halogen " or " halo " (combining separately or with other term) refer to fluorin radical (can be write as-F), cl radical (can be write as-Cl), bromine group (can be write as-Br) or iodine group (can be write as-I).
If substituting group is described to " replacement ", non-hydrogen atom group replaces the hydrogen atom group on this substituent carbon or nitrogen.Thus, for example, the alkyl substituent of replacement is that wherein at least one non-hydrogen atom group replaces the alkyl substituent that the hydrogen atom on this alkyl substituent is rolled into a ball.In order to illustrate, the alkyl that single fluoroalkyl is replaced by a fluorin radical, the alkyl that fluoroalkyl is replaced by two fluorin radicals.Should be realized that, if there is more than one replacement on substituting group, each non-hydrogen atom group can identical or different (unless otherwise mentioned).
If substituting group is described to " optional replacement ", this substituting group can be: (1) is unsubstituted, or (2) replacement.If substituting group is described to optional at the most by the replacement of the non-hydrogen atom of concrete number group, this substituting group can be: (1) is unsubstituted; Or (2) replaced by the non-hydrogen atom of this concrete number group at the most, or non-hydrogen atom group that at the most can the position of substitution number by the maximum on this substituting group replaces, but is as the criterion with less person.Thus, for example, if substituting group is described to optionally by three heteroaryls that non-hydrogen atoms group replaces at the most, have be less than three can the position of substitution any heteroaryl optionally by the most with can the as many non-hydrogen atom of the position of substitution group replacing that this heteroaryl is had.For example, tetrazyl (its have can the position of substitution) is optionally replaced by a non-hydrogen atom group at the most.In order further to illustrate, if amino nitrogen is described to optionally to be replaced by 2 non-hydrogen atoms groups at the most, primary amino nitrogen is optionally replaced by 2 non-hydrogen atoms groups at the most, and secondary amino nitrogen is optionally replaced by 1 non-hydrogen atom group at the most.
Present patent application is used term " substituting group " and " group " interchangeably.
Prefix " halo " represents that the substituting group that this prefix connects is replaced by one or more independent halogen groups of selecting.For example, haloalkyl refers to the alkyl substituent that wherein at least one hydrogen atom group is replaced by halogen group.The example of haloalkyl comprises chloromethyl, 1-bromotrifluoromethane, methyl fluoride, difluoromethyl, trifluoromethyl and 1,1,1-trifluoroethyl.Should be realized that, if substituting group is replaced by more than one halogen group, those halogen groups can identical or different (unless otherwise mentioned).
Prefix " perhalogeno " represents that the halogen group that each hydrogen atom group on substituting group that this prefix connects is independently selected replaces, that is, each hydrogen atom group on substituting group is replaced by halogen group.If all halogen groups are identical, prefix generally can show this halogen group.Thus, for example, term " perfluoro " refers to that each the hydrogen atom group on the substituting group that prefix connects is replaced by fluorin radical.In order to illustrate, term " perfluoroalkyl " refers to the alkyl substituent that wherein each hydrogen atom group is replaced by fluorin radical.
Term " carbonyl " (separately or with other term combination) refer to-C (O)-.
Term " aminocarboxyl " (combining separately or with other term) refers to-C (O)-NH 2.
Term " oxo " (combining separately or with other term) refers to (=O).
Term " oxygen base " (combining separately or with other term) refers to ether substituting group and can be write as-O-.
Term " alkyl hydroxy " (combining separately or with other term) refers to-alkyl-OH.
Term " alkylamino " (combining separately or with other term) refers to-alkyl-NH 2.
Term " alkoxyl group " (combining separately or with other term) refers to alkyl oxide substituting group, that is, and and-O-alkyl.This substituent example comprises: methoxyl group (O-CH 3), oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert.-butoxy.
Term " alkyl-carbonyl " (combining separately or with other term) refers to-C (O)-alkyl.
Term " aminoalkyl group carbonyl " (combining separately or with other term) refers to-C (O)-alkyl-NH 2.
Term " carbalkoxy " (combining separately or with other term) refers to-C (O)-O-alkyl.
Term " carbocylic radical carbonyl " (combining separately or with other term) refers to-C (O)-carbocylic radical.
Similarly, term " heterocyclic radical carbonyl " (combining separately or with other term) refers to-C (O)-heterocyclic radical.
Term " carbocylic radical alkyl-carbonyl " (combining separately or with other term) refers to-C (O)-alkyl-carbocylic radical.
Similarly, term " heterocyclic radical alkyl-carbonyl " (combining separately or with other term) refers to-C (O)-alkyl-heterocyclic radical.
Term " carbocylic radical oxygen base carbonyl " (combining separately or with other term) refers to-C (O)-O-carbocylic radical.
Term " carbocylic radical carbalkoxy " (combining separately or with other term) refers to-C (O)-O-alkyl-carbocylic radical.
Term " sulfenyl " or " thia " (combining separately or with other term) refer to thioether substituting group, that is, wherein bivalent sulfur atom replaces the ether substituting group of ether oxygen atom.Can be describe into-S-of this substituting group.For example, this " alkyl-sulphur-alkyl " refers to alkyl-S-alkyl (alkyl-sulfenyl-alkyl).
Term " mercaptan " or " sulfydryl " (combining separately or with other term) refer to sulfydryl substituting group and can be write as-SH.
Term " (thiocarbonyl group) " (combining separately or with other term) refers to the carbonyl that wherein Sauerstoffatom is replaced by sulphur.Can describe into-C of this substituting group (S)-.
Term " alkylsulfonyl " (combining separately or with other term) refers to-S (O) 2-.
Term " amino-sulfonyl " (combining separately or with other term) refers to-S (O) 2-NH 2.
Term " sulfinyl " or " sulfoxide group " (separately or with other term combination) refer to-S (O)-.
Term " heterocyclic radical " (separately or with other term combination) refer to altogether contain 3 to 14 annular atomses saturated (, " Heterocyclylalkyl "), fractional saturation (, " heterocycloalkenyl ") or the ring structure of completely unsaturated (that is, " heteroaryl ").At least one annular atoms is heteroatoms (that is, oxygen, nitrogen or sulphur), and remaining annular atoms is independently selected from carbon, oxygen, nitrogen and sulphur.Heterocyclic radical can be monocycle or polynuclear plane.
Heterocyclic radical can be monocyclic heterocycles base, and it typically contains 3 to 7 annular atomses, more typically contains 3 to 6 annular atomses, and even more typically contains 5 to 6 annular atomses.The example of monocyclic heterocycles base comprises: furyl, dihydrofuran base, tetrahydrofuran base, thienyl (sulphur furyl), dihydro-thiophene base, tetrahydro-thienyl, pyrryl, pyrrolinyl, pyrrolidyl, imidazolyl, imidazolinyl, imidazolidyl, pyrazolyl, pyrazolinyl, pyrazolidyl, triazolyl, tetrazyl, oxazolyl, oxazolidinyl, isoxazole alkyl, isoxazolyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazoline base, thiazolidyl, isothiazole alkyl, thiadiazolyl group, oxadiazolyl (comprises 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl (furazan base) or 1, 3, 4-oxadiazolyl), oxatriazole base (comprises 1, 2, 3, 4-oxatriazole base or 1, 2, 3, 5-oxatriazole base), Er oxazolyl (comprises 1, 2, 3-bis-oxazolyl, 1, 2, 4-bis-oxazolyl, 1, 3, 2-bis-oxazolyl, or 1, 3, 4-bis-oxazolyl), Evil thiazolyl, oxygen thia cyclopentenyl, oxa-thiacyclopentane base, pyranyl, dihydro pyranyl, sulphur pyranyl, tetrahydrochysene sulphur pyranyl, pyridyl (azine group), piperidyl, two azine groups (comprise pyridazinyl (1, 2-bis-azine groups), pyrimidyl (1, 3-bis-azine groups) or pyrazinyl (1, 4-bis-azine groups)), piperazinyl, triazinyl (comprises 1, 3, 5-triazinyl, 1, 2, 4-triazinyl and 1, 2, 3-triazinyl)), oxazinyl (comprises 1, 2-oxazinyl, 1, 3-oxazinyl or 1, 4-oxazinyl)), Evil thiazinyl (comprises 1, 2, 3-Evil thiazinyl, 1, 2, 4-Evil thiazinyl, 1, 2, 5-Evil thiazinyl, or 1, 2, 6-Evil thiazinyl)), oxadiazine base (comprises 1, 2, 3-oxadiazine base, 1, 2, 4-oxadiazine base, 1, 4, 2-oxadiazine base or 1, 3, 5-oxadiazine base)), morpholinyl, azepine
Figure 894161DEST_PATH_IMAGE002
base (azepinyl), oxa-
Figure 811302DEST_PATH_IMAGE002
base (oxepinyl), thia
Figure 591039DEST_PATH_IMAGE002
base (thiepinyl) and diaza
Figure 533718DEST_PATH_IMAGE002
base.
Heterocyclic radical can be also many ring heterocyclic radicals (that is, can contain more than one ring).The example of many ring heterocyclic radicals comprises bridging, condenses and Spirocyclic heterocyclic base.In Spirocyclic heterocyclic base, two different rings have an atom.In the heterocyclic radical of bridging, ring is shared at least two shared non-conterminous atoms.In fused ring heterocycle base, two or more rings can condense together, make two rings share a common key.The example of the fused ring heterocycle base that contains two or three rings comprises: indolizinyl (indolizinyl), pyrans pyrryl, 4H-quinolizinyl, purine radicals, naphthyridinyl, pyridopyridine base (comprises pyrido [3,4-b]-pyridyl, pyrido [3,2-b]-pyridyl, or pyrido [4,3-b]-pyridyl) and pteridine radicals.Other example of fused ring heterocycle base comprises: benzo-fused heterocyclic radical, indyl for example, isoindolyl (different benzo a word used for translation azoles base, false isoindolyl), pseudoindolyl (pseudoindolyl), pseudoindoyl (phenylpyrazole base), benzo azine group (comprising quinolyl (1-benzo azine group) or isoquinolyl (2-benzo azine group)), phthalazinyl, quinoxalinyl, quinazolyl, benzo two azine groups (comprise and scold Lin Ji (1, 2-benzo two azine groups) or quinazolyl (1, 3-benzo two azine groups)), benzopyranyl (comprising chromanyl or isochroman base), benzoxazinyl (comprises 1, 3, 2-benzoxazinyl, 1, 4, 2-benzoxazinyl, 2, 3, 1-benzoxazinyl, or 3, 1, 4-benzoxazinyl) and Ben Bing Yi oxazinyl (comprise 1, 2-Ben Bing Yi oxazinyl or 1, 4-Ben Bing Yi oxazinyl).
Term " Heterocyclylalkyl " (combining separately or with other term) refers to saturated heterocyclyl.
Term " heteroaryl " (combining separately or with other term) refers to the fragrant heterocyclic radical that contains 5 to 14 annular atomses.Heteroaryl can be monocycle or 2 or 3 condensed ring heteroaryls.The substituent example of heteroaryl comprises: 6 yuan of ring substituents, pyridyl for example, pyrazinyl (pyrazyl), pyrimidyl, pyridazinyl and 1,3,5-, 1,2,4-or 1,2,3-triazinyl; 5 yuan of ring substituents, imidazolyl for example, furyl, thienyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-, 1,2,4-, 1,2,5-or 1,3,4-oxadiazolyl and isothiazolyl; 6/5 yuan of fused ring substituents, benzimidazole thiophanate furyl (thienyl) for example, benzoisoxazole base, benzoxazolyl, the adjacent first lactam group of purine radicals and benzene; With 6/6 yuan of condensed ring, benzopyranyl for example, quinolyl, isoquinolyl, scolds Lin Ji, quinazolyl and benzoxazinyl.
The substituent prefix that connects a plurality of integral parts is only applicable to first integral part.For example, term " alkyl-cycloalkyl " contains two integral parts: alkyl and cycloalkyl.Thus, C 1-C 6c on-alkyl-cycloalkyl 1-C 6-prefix refers to: the alkyl integral part of alkyl-cycloalkyl contains 1 to 6 carbon atom; C 1-C 6-prefix is not described cycloalkyl integral part.Further illustrate, the prefix on halogenated alkoxy alkyl " halo " represents: only have the alkoxyl group integral part of alkyl oxy alkyl substituent to be replaced by one or more halogen groups.If halogenic substituent can or appear on alkyl integral part in addition, this substituting group is described to " the alkyl oxy alkyl that halogen replaces ", rather than " halogenated alkoxy alkyl ".Finally, if halogenic substituent only appears on alkyl integral part, this substituting group is described to " halogenated alkoxy alkyl ".
Term " treatment " refers to and alleviates or eliminate a disease and/or the method for its simultaneous phenomenon.
Term " prevention " refers to and prevents the outbreak of disease and/or its simultaneous phenomenon or avoid method that patient is fallen ill." prevention " used herein also comprises that the initial sum that postpones disease and/or its simultaneous phenomenon reduces the danger that patient falls ill.
Term " treatment significant quantity " refers to: be enough to prevent the formation of treated illness or obstacle or its one or more symptom is alleviated to the sufficient amount of the compound that to a certain degree given.
Term " adjusting " refers to that compound improves or reduce kinase whose function or active ability.Various forms of " adjusting " used herein, is intended to comprise the active antagonistic action relevant to kinases, agonism, partial antagonism and/or part agonism.Kinase inhibitor is compound, and for example, itself and stimulation combination, partially or completely blocking-up stimulation, reduce, prevent, postpone activation, and inactivation, passivation or downward conditioning signal are transduceed.Kinase activation agent be can in conjunction with, stimulate, improve, open, activate, promote, strengthen activation, sensitization or the compound of conditioning signal transduction upwards.
Term used herein " composition " comprises the product of the concrete component that contains concrete quantity, and any product can be directly or indirectly obtaining in the combination of the concrete component of concrete quantity." pharmaceutically acceptable " refer to carrier, thinner or vehicle must with other component compatibility of preparation, and harmless to its recipient.
" patient " defined herein comprises animal, and for example Mammals, includes but not limited to: primates (for example, people), ox, sheep, goat, horse, dog, cat, rabbit, rat, mouse etc.In preferred embodiments, patient is people.
compound
the embodiment of formula (I)
In one embodiment, the present invention partly relates to the compounds category with formula (I) structure
Wherein
X is N or CR 1;
Y is N or CR 2;
Z is O, S or NH;
R 1h or C 1-6-alkyl;
R 2h or C 1-6-alkyl;
R 3c 1-8-alkyl, C 2-8-thiazolinyl, C 3-8-cycloalkyl, aryl, or heteroaryl, wherein, (a) C 1-8-alkyl or C 2-8-thiazolinyl is optionally selected from following substituting group and replaces by one or more: halogen, cyano group, nitro ,-OR a,-C (O) R a,-C (O) OR a,-OC (O) R a,-NR br c,-NR bc (O) R a,-NHC (O) NHR b,-C (O) NR br c,-NHSO 2r awith-SO 2nR bnR c; (b) C 3-8-cycloalkyl, aryl and heteroaryl are optionally selected from following substituting group and replace by one or more: C 1-6-alkyl, C 1-6-haloalkyl, C 2-6-thiazolinyl, Heterocyclylalkyl, aryl, heteroaryl, halogen, oxo, cyano group, nitro ,-OR d,-C (O) R d,-C (O) OR d,-OC (O) R d,-SR d,-S (O) R d,-SO 2r d,-NR er f,-NHC (O) R e,-NHC (O) NHR e,-NHC (O) OR e,-NHSO 2r d,-C (O) NHR ewith-SO 2nHNR e;
R 4be
(a) phenyl, naphthyl, tetralyl, indenyl or indanyl, wherein phenyl, naphthyl, tetralyl, indenyl or indanyl are optionally by one or more R 5replace; Or
(b) 5-16 unit monocycle, dicyclo or tricyclic heterocyclic base, wherein heterocyclic radical is optionally by one or more R 6replace;
R 5when occurring, be CN independently at every turn, NO 2, halogen, C 1-6-alkyl, OR g, SR g, C (O) R g, C (O) NR hr i, C (O) OR g, NR hr i, NR hc (O) R g, S (O) 2r g, NR hs (O) 2r g, S (O) 2nR hr i, aryl, cycloalkyl, heteroaryl, Heterocyclylalkyl or heterocycloalkenyl, wherein C 1-6-alkyl is optionally selected from following substituting group and replaces by one or more: CN, halogen, hydroxyl, S (O) 2nH (C 1-6-alkyl), C 1-6-alkoxyl group, Heterocyclylalkyl, cycloalkyl, heteroaryl, aryl, NH 2, NHC 1-6-alkyl and-N (C 1-6-alkyl) 2; Wherein aryl, cycloalkyl, heteroaryl or Heterocyclylalkyl, separately or as the part of another part, optionally by one or more R 7replace;
R 6when occurring, be CN independently at every turn, NO 2, halogen, C 3-8cycloalkyl, OR j, SR j, C (O) R j, C (O) NR kr l, C (O) OR j, NR kr l, NR kc (O) R j, S (O) 2r j, NR ks (O) 2r jor S (O) 2nR kr l, C wherein 1-6-alkyl is optionally selected from following substituting group and replaces by one or more: CN, halogen, hydroxyl, C 1-6-alkoxyl group, Heterocyclylalkyl, cycloalkyl, heteroaryl, aryl, NH 2, NHC 1-6-alkyl and-N (C 1-6-alkyl) 2; Wherein Heterocyclylalkyl, cycloalkyl, heteroaryl, aryl, separately or as the part of another part, optionally by one, two or three replace independently selected from following substituting group: CN, halogen, heteroaryl, benzyl and C 1-6alkyl;
R 7when occurring, be CN independently at every turn, NO 2, halogen, oxo, C 1-6alkyl, aryl, C 3-8cycloalkyl, heteroaryl, Heterocyclylalkyl, OR m, SR m, C (O) R m, C (O) NR nr o, C (O) OR m, OC (O) R m, OC (O) NR nr o, NR nr o, NR nc (O) R m, S (O) R m, S (O) NR nr o, S (O) 2r m, NR ns (O) 2r mor S (O) 2nR nr o, C wherein 1-6-alkyl is optionally selected from following substituting group and replaces by one or more: CN, halogen, hydroxyl, C 1-6-alkoxyl group, Heterocyclylalkyl, cycloalkyl, aryl, heteroaryl, NH 2, NHC 1-6-alkyl and-N (C 1-6-alkyl) 2, wherein aryl, C 3-8cycloalkyl, heteroaryl and Heterocyclylalkyl, separately or as the part of another part, optionally by one, two or three replace independently selected from following substituting group: CN, halogen and C 1-6alkyl;
R awhen occurring at every turn independently selected from H, C 1-6alkyl, C 1-6haloalkyl, aryl, C 3-8cycloalkyl, heteroaryl and Heterocyclylalkyl;
R band R cwhen occurring at every turn independently selected from H, C 1-6alkyl, C 1-6haloalkyl, aryl, C 3-8cycloalkyl, heteroaryl and Heterocyclylalkyl;
R dwhen occurring at every turn independently selected from H, C 1-6alkyl, C 1-6haloalkyl, aryl, C 3-8cycloalkyl, heteroaryl and Heterocyclylalkyl;
R eand R fwhen occurring at every turn independently selected from H, C 1-6alkyl, C 1-6haloalkyl, aryl, C 3-8cycloalkyl, heteroaryl and Heterocyclylalkyl;
R gwhen occurring at every turn independently selected from H, C 1-6alkyl, aryl, C 3-8cycloalkyl, heteroaryl and Heterocyclylalkyl; C wherein 1-6-alkyl is optionally selected from following substituting group and replaces by one or more: CN, halogen, hydroxyl, C 1-6-alkoxyl group, Heterocyclylalkyl, NH 2, NHC 1-6-alkyl and-N (C 1-6-alkyl) 2, wherein aryl, C 3-8cycloalkyl, heteroaryl or Heterocyclylalkyl, separately or as the part of another part, be optionally selected from following substituting group and replace by one or more: halogen, C 1-6-alkyl, C 1-6-haloalkyl, C 1-6-hydroxyalkyl, hydroxyl, oxo, C 1-6-alkoxyl group, C 1-6-halogenated alkoxy, C (O) C 1-6-alkyl, S (O) 2c 1-6-alkyl, NH 2, NH (C 1-6-alkyl), N (C 1-6-alkyl) 2and N (C 1-6-alkyl) (C 3-8-cycloalkyl);
R hand R iwhen occurring at every turn independently selected from H, C 1-6alkyl, aryl, C 3-8cycloalkyl, heteroaryl and Heterocyclylalkyl; C wherein 1-6-alkyl is optionally selected from following substituting group and replaces by one or more: CN, halogen, hydroxyl, C 1-6-alkoxyl group, Heterocyclylalkyl, NH 2, NHC 1-6-alkyl and-N (C 1-6-alkyl) 2, wherein aryl, C 3-8cycloalkyl, heteroaryl or Heterocyclylalkyl, separately or as the part of another part, be optionally selected from following substituting group and replace by one or more: halogen, C 1-6-alkyl, C 1-6-haloalkyl, C 1-6-hydroxyalkyl, hydroxyl, oxo, C 1-6-alkoxyl group, C 1-6-halogenated alkoxy, C (O) C 1-6-alkyl, S (O) 2c 1-6-alkyl, NH 2, NH (C 1-6-alkyl), N (C 1-6-alkyl) 2and N (C 1-6-alkyl) (C 3-8-cycloalkyl);
R jwhen occurring at every turn independently selected from H, C 1-6alkyl, aryl, C 3-8cycloalkyl, heteroaryl and Heterocyclylalkyl; C wherein 1-6-alkyl is optionally selected from following substituting group and replaces by one or more: halogen, hydroxyl, C 1-6-alkoxyl group, NH 2, NHC 1-6-alkyl and-N (C 1-6-alkyl) 2, wherein aryl, C 3-8cycloalkyl, heteroaryl or Heterocyclylalkyl are optionally selected from following substituting group and replace by one or more: halogen, C 1-6-alkyl, C 1-6-haloalkyl, C 1-6-hydroxyalkyl, hydroxyl, oxo, C 1-6-alkoxyl group, C 1-6-halogenated alkoxy, NH 2, NH (C 1-6-alkyl) and N (C 1-6-alkyl) 2;
R kand R lwhen occurring at every turn independently selected from H, C 1-6alkyl, aryl, C 3-8cycloalkyl, heteroaryl and Heterocyclylalkyl; C wherein 1-6-alkyl is optionally selected from following substituting group and replaces by one or more: halogen, hydroxyl, C 1-6-alkoxyl group, NH 2, NHC 1-6-alkyl and-N (C 1-6-alkyl) 2, wherein aryl, C 3-8cycloalkyl, heteroaryl or Heterocyclylalkyl are optionally selected from following substituting group and replace by one or more: halogen, C 1-6-alkyl, C 1-6-haloalkyl, C 1-6-hydroxyalkyl, hydroxyl, oxo, C 1-6-alkoxyl group, C 1-6-halogenated alkoxy, NH 2, NH (C 1-6-alkyl) and N (C 1-6-alkyl) 2;
R mwhen occurring at every turn independently selected from H, C 1-6alkyl, aryl, C 3-8cycloalkyl, heteroaryl and Heterocyclylalkyl; C wherein 1-6-alkyl is optionally selected from following substituting group and replaces by one or more: halogen, hydroxyl, C 1-6-alkoxyl group, NH 2, NHC 1-6-alkyl and-N (C 1-6-alkyl) 2, wherein aryl, C 3-8cycloalkyl, heteroaryl or Heterocyclylalkyl are optionally selected from following substituting group and replace by one or more: halogen, C 1-6-alkyl, C 1-6-haloalkyl, C 1-6-hydroxyalkyl, hydroxyl, oxo, C 1-6-alkoxyl group, C 1-6-halogenated alkoxy, NH 2, NH (C 1-6-alkyl) and N (C 1-6-alkyl) 2;
R nand R owhen occurring at every turn independently selected from H, C 1-6alkyl, aryl, C 3-8cycloalkyl, heteroaryl and Heterocyclylalkyl; C wherein 1-6-alkyl is optionally selected from following substituting group and replaces by one or more: halogen, hydroxyl, C 1-6-alkoxyl group, NH 2, NHC 1-6-alkyl and-N (C 1-6-alkyl) 2, wherein aryl, C 3-8cycloalkyl, heteroaryl or Heterocyclylalkyl are optionally selected from following substituting group and replace by one or more: halogen, C 1-6-alkyl, C 1-6-haloalkyl, C 1-6-hydroxyalkyl, hydroxyl, oxo, C 1-6-alkoxyl group, C 1-6-halogenated alkoxy, NH 2, NH (C 1-6-alkyl) and N (C 1-6-alkyl) 2;
Or its pharmacologically acceptable salt or solvate;
Condition is that described compound is not 6-(2,6-3,5-dimethylphenyl)-2-((4-(4-methyl isophthalic acid-piperazinyl) phenyl) amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one.
In an embodiment of formula (I), X is CR 1, Y is CR 2.In another embodiment of formula (I), X is CR 1, Y is CR 2, R 1h, R 2h.In another embodiment of formula (I), X is CR 1, Y is CR 2, R 1c 1-6alkyl, R 2h.In another embodiment of formula (I), X is CR 1, Y is CR 2, R 1h, R 2c 1-6alkyl.In another embodiment of formula (I), X is CR 1, Y is CR 2, R 1c 1-6alkyl, R 2c 1-6alkyl.
In another embodiment of formula (I), X is N, and Y is CR 2.In another embodiment of formula (I), X is N, and Y is CR 2, R 2h.In another embodiment of formula (I), X is N, and Y is CR 2, R 2c 1-6alkyl.
In another embodiment of formula (I), X is N, and Y is N.
In an embodiment of formula (I), Z is O.
In an embodiment of formula (I), R 3c 1-8-alkyl or C 2-8-thiazolinyl, wherein C 1-8-alkyl or C 2-8-thiazolinyl is optionally selected from following substituting group and replaces by one or more: halogen, cyano group, nitro ,-OR a,-C (O) R a,-C (O) OR a,-OC (O) R a,-NR br c,-NR bc (O) R a,-NHC (O) NHR b,-C (O) NR br c,-NHSO 2r awith-SO 2nR bnR c.In another embodiment of formula (I), R 3c 1-8-alkyl or C 2-8-thiazolinyl, wherein C 1-8-alkyl or C 2-8-thiazolinyl is unsubstituted.In another embodiment of formula (I), R 3be-CH 3,-CH 2cH 3,-CH 2cH 2cH 3,-CH 2cH 2cH 2cH 3,-CH (CH 3) 2,-CH 2cH (CH 3) 2,-CH 2cH=CH 2or-CH 2cH 2cH=CH 2.
In an embodiment of formula (I), R 3c 3-8cycloalkyl, wherein C 3-8cycloalkyl is optionally selected from following substituting group and replaces by one or more: C 1-6-alkyl, C 1-6-haloalkyl, C 2-6-thiazolinyl, Heterocyclylalkyl, aryl, heteroaryl, halogen, oxo, cyano group, nitro ,-OR d,-C (O) R d,-C (O) OR d,-OC (O) R d,-SR d,-S (O) R d,-SO 2r d,-NR er f,-NHC (O) R e,-NHC (O) NHR e,-NHC (O) OR e,-NHSO 2r d,-C (O) NHR ewith-SO 2nHNR e.In another embodiment of formula (I), R 3optionally by one or more, are selected from following substituting group and replace: C 1-6-alkyl, C 1-6-haloalkyl, Heterocyclylalkyl, aryl, halogen, cyano group and-OR d.In another embodiment, R 3unsubstituted C 3-8cycloalkyl.
In an embodiment of formula (I), R 3be heteroaryl, wherein heteroaryl is optionally selected from following substituting group and replaces by one or more: C 1-6-alkyl, C 1-6-haloalkyl, C 2-6-thiazolinyl, Heterocyclylalkyl, aryl, heteroaryl, halogen, oxo, cyano group, nitro ,-OR d,-C (O) R d,-C (O) OR d,-OC (O) R d,-SR d,-S (O) R d,-SO 2r d,-NR er f,-NHC (O) R e,-NHC (O) NHR e,-NHC (O) OR e,-NHSO 2r d,-C (O) NHR ewith-SO 2nHNR e.In another embodiment, R 3be heteroaryl, wherein heteroaryl is pyridyl, furyl, thienyl, pyrryl, pyrazolyl, pyrazinyl, imidazolyl, indyl, tetrazyl ， isoxazolyl ， oxazolyl ， oxadiazolyl, thiadiazolyl group, thiazolyl or triazolyl.
In an embodiment of formula (I), R 3be aryl, wherein aryl is optionally selected from following substituting group and replaces by one or more: C 1-6-alkyl, C 1-6-haloalkyl, C 2-6-thiazolinyl, Heterocyclylalkyl, aryl, heteroaryl, halogen, oxo, cyano group, nitro ,-OR d,-C (O) R d,-C (O) OR d,-OC (O) R d,-SR d,-S (O) R d,-SO 2r d,-NR er f,-NHC (O) R e,-NHC (O) NHR e,-NHC (O) OR e,-NHSO 2r d,-C (O) NHR ewith-SO 2nHNR e.In another embodiment of formula (I), R 3be aryl, wherein aryl is selected from phenyl, naphthyl, indenyl, indanyl and tetralyl.In another embodiment of formula (I), R 3it is phenyl.In another embodiment of formula (I), R 3be phenyl, it is optionally selected from following substituting group and replaces by one or more: halogen, C 1-6alkyl, C 1-6haloalkyl ,-OC 1-6alkyl or-OC 1-6haloalkyl.In another embodiment of formula (I), R 3by one, being selected from following substituting group replaces: halogen, C 1-6alkyl, C 1-6haloalkyl ,-OC 1-6alkyl or-OC 1-6haloalkyl.In another embodiment of formula (I), R 3be , R wherein pbe selected from halogen, C 1-6alkyl, C 1-6haloalkyl ,-OC 1-6alkyl or-OC 1-6haloalkyl.In another embodiment of formula (I), R pit is halogen.In another embodiment of formula (I), R 3be
Figure 2012800188626100002DEST_PATH_IMAGE005
, R wherein pand R qindependently selected from halogen, C 1-6alkyl, C 1-6haloalkyl ,-OC 1-6alkyl or-OC 1-6haloalkyl.In another embodiment of formula (I), R pand R qit is all halogen.
In an embodiment of formula (I), R 4phenyl, naphthyl, tetralyl, indenyl or indanyl, wherein phenyl, naphthyl, tetralyl, indenyl or indanyl are optionally by one or more R 5replace; And CN, NO 2, halogen, C 1-6-alkyl, OR g, SR g, C (O) R g, C (O) NR hr i, C (O) OR g, NR hr i, NR hc (O) R g, S (O) 2r g, NR hs (O) 2r g, S (O) 2nR hr i, aryl, cycloalkyl, heteroaryl, Heterocyclylalkyl or heterocycloalkenyl, wherein C 1-6-alkyl is optionally selected from following substituting group and replaces by one or more: CN, halogen, hydroxyl, S (O) 2nH (C 1-6-alkyl), C 1-6-alkoxyl group, Heterocyclylalkyl, cycloalkyl, heteroaryl, aryl, NH 2, NHC 1-6-alkyl and-N (C 1-6-alkyl) 2; Wherein aryl, cycloalkyl, heteroaryl or Heterocyclylalkyl, separately or as the part of another part, optionally by one, two or three R 7replace; R wherein 7cN, NO 2, halogen, oxo, C 1-6alkyl, aryl, C 3-8cycloalkyl, heteroaryl, Heterocyclylalkyl, OR m, SR m, C (O) R m, C (O) NR nr o, C (O) OR m, OC (O) R m, OC (O) NR nr o, NR nr o, NR nc (O) R m, S (O) R m, S (O) NR nr o, S (O) 2r m, NR ns (O) 2r mor S (O) 2nR nr o, C wherein 1-6-alkyl is optionally selected from following substituting group and replaces by one or more: CN, halogen, hydroxyl, C 1-6-alkoxyl group, Heterocyclylalkyl, cycloalkyl, aryl, heteroaryl, NH 2, NHC 1-6-alkyl and-N (C 1-6-alkyl) 2, wherein aryl, C 3-8cycloalkyl, heteroaryl and Heterocyclylalkyl, separately or as the part of another part, optionally by one, two or three replace independently selected from following substituting group: CN, halogen and C 1-6alkyl.In another embodiment of formula (I), R 4naphthyl, tetralyl, indenyl or indanyl, wherein naphthyl, tetralyl, indenyl or indanyl are unsubstituted.In another embodiment of formula (I), R 4naphthyl, tetralyl, indenyl or indanyl, wherein naphthyl, tetralyl, indenyl or indanyl by one, two or three are selected from following substituting group and replace: CN, NO 2, halogen, C 1-6-alkyl, C 1-6-haloalkyl, OR g, SR g, C (O) R g, C (O) NR hr i, C (O) OR g, NR hr i, NR hc (O) R g, S (O) 2r g, NR hs (O) 2r gand S (O) 2nR hr i.
In an embodiment of formula (I), R 4it is phenyl.In another embodiment of formula (I), R 4be phenyl, wherein phenyl is unsubstituted.In another embodiment of formula (I), R 4be phenyl, wherein phenyl is by one, two or three R 5replace R 5cN, NO 2, halogen, C 1-6-alkyl, OR g, SR g, C (O) R g, C (O) NR hr i, C (O) OR g, NR hr i, NR hc (O) R g, S (O) 2r g, NR hs (O) 2r g, S (O) 2nR hr i, aryl, cycloalkyl, heteroaryl, Heterocyclylalkyl or heterocycloalkenyl, wherein C 1-6-alkyl is optionally selected from following substituting group and replaces by one or more: CN, halogen, hydroxyl, S (O) 2nH (C 1-6-alkyl), C 1-6-alkoxyl group, Heterocyclylalkyl, cycloalkyl, heteroaryl, aryl, NH 2, NHC 1-6-alkyl and-N (C 1-6-alkyl) 2; Wherein aryl, cycloalkyl, heteroaryl or Heterocyclylalkyl, separately or as the part of another part, optionally by one, two or three R 7replace; R wherein 7cN, NO 2, halogen, oxo, C 1-6alkyl, aryl, C 3-8cycloalkyl, heteroaryl, Heterocyclylalkyl, OR m, SR m, C (O) R m, C (O) NR nr o, C (O) OR m, OC (O) R m, OC (O) NR nr o, NR nr o, NR nc (O) R m, S (O) R m, S (O) NR nr o, S (O) 2r m, NR ns (O) 2r mor S (O) 2nR nr o, C wherein 1-6-alkyl is optionally selected from following substituting group and replaces by one or more: CN, halogen, hydroxyl, C 1-6-alkoxyl group, Heterocyclylalkyl, cycloalkyl, aryl, heteroaryl, NH 2, NHC 1-6-alkyl and-N (C 1-6-alkyl) 2, wherein aryl, C 3-8cycloalkyl, heteroaryl and Heterocyclylalkyl, separately or as the part of another part, optionally by one, two or three replace independently selected from following substituting group: CN, halogen and C 1-6alkyl.In another embodiment of formula (I), R 7c 1-6-alkyl, C 1-6haloalkyl, or C (O) R m; R mc 1-6alkyl, C 1-6haloalkyl or C 3-8cycloalkyl.
In an embodiment of formula (I), R 4be phenyl, wherein phenyl is by Heterocyclylalkyl and optional one or two R 5replace, wherein R 5halogen, C 1-6alkyl, C 1-6haloalkyl or OR g, wherein Heterocyclylalkyl is optionally by one, two or three R 7replace; R wherein 7cN, NO 2, halogen, oxo, C 1-6alkyl, aryl, C 3-8cycloalkyl, heteroaryl, Heterocyclylalkyl, OR m, SR m, C (O) R m, C (O) NR nr o, C (O) OR m, OC (O) R m, OC (O) NR nr o, NR nr o, NR nc (O) R m, S (O) R m, S (O) NR nr o, S (O) 2r m, NR ns (O) 2r mor S (O) 2nR nr o, C wherein 1-6-alkyl is optionally selected from following substituting group and replaces by one or more: CN, halogen, hydroxyl, C 1-6-alkoxyl group, Heterocyclylalkyl, cycloalkyl, aryl, heteroaryl, NH 2, NHC 1-6-alkyl and-N (C 1-6-alkyl) 2, wherein aryl, C 3-8cycloalkyl, heteroaryl and Heterocyclylalkyl, separately or as the part of another part, optionally by one, two or three replace independently selected from following substituting group: CN, halogen and C 1-6alkyl.In another embodiment of formula (I), R 5heterocyclylalkyl is piperazinyl, Diazesuberane base, piperidyl, pyrrolidyl, morpholinyl, hexahydropyrrolo also [1, 2-a] pyrazinyl, oxo piperazinyl, (1S, 4S)-2, 5-diazabicyclo [2.2.1] heptan-2-base, (1R, 4R)-2, 5-diazabicyclo [2.2.1] heptan-2-base, 6-oxo-1, 4, 5, 6-tetrahydro pyridazine-3-base, octahydro-2H-quinolizinyl, 3, 7-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-3-base, (8aR)-hexahydropyrrolo also [1, 2-a] pyrazine-2 (1H)-Ji, octahydro-2H-pyrido [1, 2-a] pyrazine-2-base, thiazolidine-2-Ji, 4-oxo-1, 3-thiazolidine-2-Ji, (3R)-1-azabicyclo [2.2.2] oct-3-yl or thio-morpholinyl.
In another embodiment of formula (I), R 4be
Figure 232870DEST_PATH_IMAGE006
Figure 2012800188626100002DEST_PATH_IMAGE007
Figure 814417DEST_PATH_IMAGE008
Figure DEST_PATH_IMAGE009
Figure 888684DEST_PATH_IMAGE010
。
R wherein 5halogen, C 1-6-alkyl, C 1-6haloalkyl or OR g; P is 0 or 1; R 7cN, NO 2, halogen, C 1-6-alkyl, C 1-6-haloalkyl, OR m, SR m, C (O) R m, C (O) NR nr o, C (O) OR m, NR nr o, NR nc (O) R m, S (O) 2r m, NR ns (O) 2r mor S (O) 2nR mr o; Q is 0 or 1.
In an embodiment of formula (I), R 3be phenyl, wherein phenyl is selected from following substituting group by one and replaces: C 1-6-alkyl, C 1-6-haloalkyl, halogen and OR d;
R 4be
Figure DEST_PATH_IMAGE011
; R 5halogen, C 1-6-alkyl, C 1-6haloalkyl or OR g; P is 0 or 1.
In an embodiment of formula (I), R 4be
Figure 557563DEST_PATH_IMAGE012
R wherein 5halogen, C 1-6alkyl, C 1-6haloalkyl or OR g; R gbe selected from H, C 1-6alkyl, aryl, C 3-8cycloalkyl, heteroaryl and Heterocyclylalkyl; C wherein 1-6-alkyl is optionally selected from following substituting group and replaces by one or more: CN, halogen, hydroxyl, C 1-6-alkoxyl group, Heterocyclylalkyl, NH 2, NHC 1-6-alkyl and-N (C 1-6-alkyl) 2, wherein aryl, C 3-8cycloalkyl, heteroaryl or Heterocyclylalkyl, separately or as the part of another part, be optionally selected from following substituting group and replace by one or more: halogen, C 1-6-alkyl, C 1-6-haloalkyl, C 1-6-hydroxyalkyl, hydroxyl, oxo, C 1-6-alkoxyl group, C 1-6-halogenated alkoxy ,-C (O) C 1-6-alkyl ,-S (O) 2c 1-6-alkyl ,-NH 2,-NH (C 1-6-alkyl) ,-N (C 1-6-alkyl) 2with-N (C 1-6-alkyl) (C 3-8-cycloalkyl); R hand R iwhen occurring at every turn independently selected from H, C 1-6alkyl, aryl, C 3-8cycloalkyl, heteroaryl and Heterocyclylalkyl; C wherein 1-6-alkyl is optionally selected from following substituting group and replaces by one or more: CN, halogen, hydroxyl, C 1-6-alkoxyl group, Heterocyclylalkyl ,-NH 2,-NHC 1-6-alkyl and-N (C 1-6-alkyl) 2, wherein aryl, C 3-8cycloalkyl, heteroaryl or Heterocyclylalkyl, separately or as the part of another part, be optionally selected from following substituting group and replace by one or more: halogen, C 1-6-alkyl, C 1-6-haloalkyl, C 1-6-hydroxyalkyl, hydroxyl, oxo, C 1-6-alkoxyl group, C 1-6-halogenated alkoxy ,-C (O) C 1-6-alkyl ,-S (O) 2c 1-6-alkyl ,-NH 2,-NH (C 1-6-alkyl), N (C 1-6-alkyl) 2with-N (C 1-6-alkyl) (C 3-8-cycloalkyl); P is 0,1 or 2.
In an embodiment of formula (I), R 4be 5-16 unit monocycle, dicyclo or tricyclic heterocyclic base, wherein heterocyclic radical is optionally by one or more R 6replace R 6cN, NO 2, halogen, C 3-8cycloalkyl, OR j, SR j, C (O) R j, C (O) NR kr l, C (O) OR j, NR kr l, NR kc (O) R j, S (O) 2r j, NR ks (O) 2r jor S (O) 2nR kr l, C wherein 1-6-alkyl is optionally selected from following substituting group and replaces by one or more: CN, halogen, hydroxyl, C 1-6-alkoxyl group, Heterocyclylalkyl, cycloalkyl, heteroaryl, aryl ,-NH 2,-NHC 1-6-alkyl and-N (C 1-6-alkyl) 2; Wherein Heterocyclylalkyl, cycloalkyl, heteroaryl, aryl, separately or as the part of another part, optionally by one, two or three replace independently selected from following substituting group: CN, halogen, heteroaryl, benzyl and C 1-6alkyl.
In an embodiment of formula (I), R 4it is 4-8 unit monocyclic heterocycles base.In another embodiment, R 44-8 unit's Heterocyclylalkyl or heterocycloalkenyl.In another embodiment, R 4it is 5-7 unit heteroaryl.In another embodiment of formula (I), R 4pyrrolidyl, tetrahydrofuran base, tetrahydro-thienyl, imidazolidyl, pyrazolidyl, piperidyl, Diazesuberane base, THP trtrahydropyranyl, piperazinyl, alkyl dioxin, thiazolidine-2-Ji, morpholinyl, 2-oxo-pyrrolidine base, 4-oxo-1,3-thiazoles alkane-2-base, thio-morpholinyl, 2,5-dioxo pyrrolidyl, 2-oxo-piperidine base, 4-oxo-piperidine base or 2,6-dioxopiperidine base.In another embodiment of formula (I), R 4pyridyl (pyridyl), pyrazinyl (pyrazyl), pyridyl (pyridinyl), pyrimidyl, pyridazinyl, 1,3,5-, 1,2,4-or 1,2,3-triazinyl, imidazolyl (imidazyl), furyl, thienyl, pyrazolyl ， oxazolyl ， isoxazolyl, thiazolyl, 1,2,3-, 1,2,4-, 1,2,5-or 1,3,4-oxadiazolyl, or isothiazolyl.In one embodiment, R 4unsubstituted.In another embodiment, R 4by one, two or three R 6replace R 6halogen, C 1-6-alkyl, C 1-6-haloalkyl, OR j, C (O) R j, NR kr lor S (O) 2r j.
In an embodiment of formula (I), R 4it is 7-11 unit bicyclic heterocyclic radical.In another embodiment, R 47-11 unit's bicyclic heterocycle alkyl or bicyclic heterocycle thiazolinyl.In another embodiment, R 4it is 7-11 unit bicyclic heteroaryl.In another embodiment, R 42, 3-dihydro-2-oxo--1H-indyl, hexahydropyrrolo also [1, 2-a] pyrazinyl, (1R, 4R)-2, 5-diazabicyclo [2.2.1] heptan-2-base, benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolyl, quinolyl-N-oxide compound, tetrahydro isoquinolyl, isoquinolyl, benzimidazolyl-, benzopyranyl, indolizinyl, benzofuryl, chromone base, tonka bean camphor base, scold Lin Ji, quinoxalinyl, indazolyl, pyrrolopyridinyl, furo pyridyl, dihydro-iso indolyl, dihydroquinazoline base, 3, 4-dihydro-4-oxo-quinazolyl, 6-oxo-1, 4, 5, 6-tetrahydro pyridazine-3-base, octahydro-2H-quinolizinyl, 3, 7-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-3-base, (8aR)-hexahydropyrrolo also [1, 2-a] pyrazine-2 (1H)-Ji, benzisothiazole base, benzoisoxazole base, benzo two azine groups, benzofuraxan base, benzothiopyran base, octahydro-2H-pyrido [1, 2-a] pyrazine-2-base, benzotriazole base, phenylpyrazole base, 1, 3-benzodioxole base, (3R)-1-azabicyclo [2.2.2] oct-3-yl, dihydro benzo furyl, dihydrobenzo thienyl, dihydrobenzo sulphur pyranyl, dihydrobenzo sulphur pyranyl sulfone, dihydrobenzopyrans base, Er hydrogen benzoxazinyl, 3-oxo-3, 4-dihydro-1, 4-benzoxazinyl, indolinyl, indazolyl, 4-oxo-1, 4-dihydro cinnolines-6-base, isochroman base, iso-dihydro-indole-group, naphthyridinyl, phthalazinyl, piperonyl, purine radicals, pyridopyridine base, pyrrolotriazine base, quinazolyl, 1, 2, 3-diazosulfide base-5-base, 1, 3-benzothiazol-6-yl, tetrahydric quinoline group, thienofuran base, thienopyridine base, [1, 2-a] pyridine-2-base, 2, 3-glyoxalidine also [2, 1-b] [1, 3] thiazole-6-base, imidazo [2, 1-b] [1, 3] thiazole-6-base, 3-oxo-2, 3-dihydro-1H-indazole-7-base, 5, 6, 7, 8-tetrahydrochysene-1, 6-naphthyridines-3-base, 2, 7-diaza spiro [3.5] ninth of the ten Heavenly Stems-7-base, 2, 6-diaza spiro [3.3] heptan-2-base, 2, 6-diaza spiro [3.4] is pungent-2-base, 2, 7-diaza spiro [3.5] ninth of the ten Heavenly Stems-2-base, 3, 0-diaza spiro [5.5] 10 one-3-bases, (3aR, 6aR)-hexahydropyrrolo also [3, 4-b] pyrroles-1 (2H)-Ji, 2, 3, 4, 5-tetrahydrochysene-1H-2-benzo-aza
Figure 613243DEST_PATH_IMAGE002
base, 2,3,4,5-tetrahydrochysene-1H-3-benzo-aza base, 1,2,3,4-tetrahydroisoquinoline-7-base, 1,2,3,4-tetrahydric quinoline group, 4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-base, 2,3-dihydro-1H-indoles-5-base, indolinyl, 2,3-dihydro-1H-indazolyl, isoindolinyl, 1,2,3,4-tetrahydroisoquinoline-6-base or thienothiophene base.In an embodiment of formula (I), R 4unsubstituted.In another embodiment of formula (I), R 4by one, two or three R 6replace R 6cN, NO 2, halogen, C 3-8cycloalkyl, OR j, SR j, C (O) R j, C (O) NR kr l, C (O) OR j, NR kr l, NR kc (O) R j, S (O) 2r j, NR ks (O) 2r jor S (O) 2nR kr l, C wherein 1-6-alkyl is optionally selected from following substituting group and replaces by one or more: CN, halogen, hydroxyl, C 1-6-alkoxyl group, Heterocyclylalkyl, cycloalkyl, heteroaryl, aryl ,-NH 2,-NHC 1-6-alkyl and-N (C 1-6-alkyl) 2; Wherein Heterocyclylalkyl, cycloalkyl, heteroaryl, aryl, separately or as the part of another part, optionally by one, two or three replace independently selected from following substituting group: CN, halogen, heteroaryl, benzyl and C 1-6alkyl.
In an embodiment of formula (I), R 4be
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or
。
In an embodiment of formula (I), R 4it is 10-15 unit tricyclic heterocyclic base.In another embodiment, R 410-15 unit's tricyclic heterocyclic alkyl or tricyclic heterocyclic thiazolinyl.In another embodiment, R 4it is 10-15 unit tricyclic heteroaryl.In an embodiment of formula (I), R 4be 5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base or 2' also, 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-base.In an embodiment of formula (I), R 4unsubstituted.In another embodiment of formula (I), R 4by one, two or three R 6replace R 6halogen, C 1-6-alkyl, C 1-6-haloalkyl, OR j, C (O) R j, NR kr lor S (O) 2r j.
In an embodiment of formula (I), R 4be
Figure DEST_PATH_IMAGE021
。
the embodiment of formula (II)
In one embodiment, the present invention partly relates to the compounds category with formula (II) structure
Figure 132485DEST_PATH_IMAGE022
R wherein 1, R 2, R 3and R 4described in formula (I), condition is that described compound is not 6-(2,6-3,5-dimethylphenyl)-2-((4-(4-methyl isophthalic acid-piperazinyl) phenyl) amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one.
In an embodiment of formula (II), R 1h, R 2h.In another embodiment of formula (II), R 1c 1-6alkyl, R 2h.In another embodiment of formula (II), R 1h, R 2c 1-6alkyl.In another embodiment of formula (II), R 1c 1-6alkyl, R 2c 1-6alkyl.
In an embodiment of formula (II), R 3be aryl, wherein aryl is optionally selected from following substituting group and replaces by one or more: C 1-6-alkyl, C 1-6-haloalkyl, C 2-6-thiazolinyl, Heterocyclylalkyl, aryl, heteroaryl, halogen, oxo, cyano group, nitro ,-OR d,-C (O) R d,-C (O) OR d,-OC (O) R d,-SR d,-S (O) R d,-SO 2r d,-NR er f,-NHC (O) R e,-NHC (O) NHR e,-NHC (O) OR e,-NHSO 2r d,-C (O) NHR ewith-SO 2nHNR e.In another embodiment of formula (II), R 3be aryl, wherein aryl is selected from phenyl, naphthyl, indenyl, indanyl and tetralyl.In another embodiment of formula (II), R 3it is phenyl.In another embodiment of formula (II), R 3be phenyl, it is optionally selected from following substituting group and replaces by one or more: halogen, C 1-6alkyl, C 1-6haloalkyl ,-OC 1-6alkyl and-OC 1-6haloalkyl.In another embodiment of formula (II), R 3by one, be selected from the phenyl that following substituting group replaces: halogen, C 1-6alkyl, C 1-6haloalkyl ,-OC 1-6alkyl and-OC 1-6haloalkyl.In another embodiment of formula (II), R 3be
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, R wherein pbe selected from halogen, C 1-6alkyl, C 1-6haloalkyl ,-OC 1-6alkyl and-OC 1-6haloalkyl.In another embodiment of formula (II), R pit is halogen.In another embodiment of formula (I), R 3be
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, R wherein pand R qindependently selected from halogen, C 1-6alkyl, C 1-6haloalkyl ,-OC 1-6alkyl or-OC 1-6haloalkyl.In another embodiment of formula (I), R pand R qit is all halogen.
In an embodiment of formula (II), R 4phenyl, naphthyl, tetralyl, indenyl or indanyl, wherein phenyl, naphthyl, tetralyl, indenyl or indanyl are optionally by one or more R 5replace; And CN, NO 2, halogen, C 1-6-alkyl, OR g, SR g, C (O) R g, C (O) NR hr i, C (O) OR g, NR hr i, NR hc (O) R g, S (O) 2r g, NR hs (O) 2r g, S (O) 2nR hr i, aryl, cycloalkyl, heteroaryl, Heterocyclylalkyl or heterocycloalkenyl, wherein C 1-6-alkyl is optionally selected from following substituting group and replaces by one or more: CN, halogen, hydroxyl, S (O) 2nH (C 1-6-alkyl), C 1-6-alkoxyl group, Heterocyclylalkyl, cycloalkyl, heteroaryl, aryl ,-NH 2,-NHC 1-6-alkyl and-N (C 1-6-alkyl) 2; Wherein aryl, cycloalkyl, heteroaryl or Heterocyclylalkyl, separately or as the part of another part, optionally by one, two or three R 7replace; R wherein 7cN, NO 2, halogen, oxo, C 1-6alkyl, aryl, C 3-8cycloalkyl, heteroaryl, Heterocyclylalkyl, OR m, SR m, C (O) R m, C (O) NR nr o, C (O) OR m, OC (O) R m, OC (O) NR nr o, NR nr o, NR nc (O) R m, S (O) R m, S (O) NR nr o, S (O) 2r m, NR ns (O) 2r mor S (O) 2nR nr o, C wherein 1-6-alkyl is optionally selected from following substituting group and replaces by one or more: CN, halogen, hydroxyl, C 1-6-alkoxyl group, Heterocyclylalkyl, cycloalkyl, aryl, heteroaryl ,-NH 2,-NHC 1-6-alkyl and-N (C 1-6-alkyl) 2, wherein aryl, C 3-8cycloalkyl, heteroaryl and Heterocyclylalkyl, separately or as the part of another part, optionally by one, two or three replace independently selected from following substituting group: CN, halogen and C 1-6alkyl.In another embodiment of formula (II), R 4naphthyl, tetralyl, indenyl or indanyl, wherein naphthyl, tetralyl, indenyl or indanyl are unsubstituted.In another embodiment of formula (II), R 4naphthyl, tetralyl, indenyl or indanyl, wherein naphthyl, tetralyl, indenyl or indanyl by one, two or three are selected from following substituting group and replace: CN, NO 2, halogen, C 1-6-alkyl, C 1-6-haloalkyl, OR g, SR g, C (O) R g, C (O) NR hr i, C (O) OR g, NR hr i, NR hc (O) R g, S (O) 2r g, NR hs (O) 2r gand S (O) 2nR hr i.
In an embodiment of formula (II), R 4it is phenyl.In another embodiment of formula (II), R 4be phenyl, wherein phenyl is unsubstituted.In another embodiment of formula (II), R 4be phenyl, wherein phenyl is by one, two or three R 5replace R 5cN, NO 2, halogen, C 1-6-alkyl, OR g, SR g, C (O) R g, C (O) NR hr i, C (O) OR g, NR hr i, NR hc (O) R g, S (O) 2r g, NR hs (O) 2r g, S (O) 2nR hr i, aryl, cycloalkyl, heteroaryl, Heterocyclylalkyl or heterocycloalkenyl, wherein C 1-6-alkyl is optionally selected from following substituting group and replaces by one or more: CN, halogen, hydroxyl, S (O) 2nH (C 1-6-alkyl), C 1-6-alkoxyl group, Heterocyclylalkyl, cycloalkyl, heteroaryl, aryl ,-NH 2,-NHC 1-6-alkyl and-N (C 1-6-alkyl) 2; Wherein aryl, cycloalkyl, heteroaryl or Heterocyclylalkyl, separately or as the part of another part, optionally by one, two or three R 7replace; R wherein 7cN, NO 2, halogen, oxo, C 1-6alkyl, aryl, C 3-8cycloalkyl, heteroaryl, Heterocyclylalkyl, OR m, SR m, C (O) R m, C (O) NR nr o, C (O) OR m, OC (O) R m, OC (O) NR nr o, NR nr o, NR nc (O) R m, S (O) R m, S (O) NR nr o, S (O) 2r m, NR ns (O) 2r mor S (O) 2nR nr o, C wherein 1-6-alkyl is optionally selected from following substituting group and replaces by one or more: CN, halogen, hydroxyl, C 1-6-alkoxyl group, Heterocyclylalkyl, cycloalkyl, aryl, heteroaryl ,-NH 2,-NHC 1-6-alkyl and-N (C 1-6-alkyl) 2, wherein aryl, C 3-8cycloalkyl, heteroaryl and Heterocyclylalkyl, separately or as the part of another part, optionally by one, two or three replace independently selected from following substituting group: CN, halogen and C 1-6alkyl.In another embodiment of formula (II), R 7c 1-6-alkyl, C 1-6haloalkyl, or C (O) R m; R mc 1-6alkyl, C 1-6haloalkyl or C 3-8cycloalkyl.
In an embodiment of formula (II), R 4be phenyl, wherein phenyl is by Heterocyclylalkyl and optional one or two R 5replace, wherein R 5halogen, C 1-6alkyl, C 1-6haloalkyl or OR g, wherein Heterocyclylalkyl is optionally by one, two or three R 7replace; R wherein 7cN, NO 2, halogen, oxo, C 1-6alkyl, aryl, C 3-8cycloalkyl, heteroaryl, Heterocyclylalkyl, OR m, SR m, C (O) R m, C (O) NR nr o, C (O) OR m, OC (O) R m, OC (O) NR nr o, NR nr o, NR nc (O) R m, S (O) R m, S (O) NR nr o, S (O) 2r m, NR ns (O) 2r mor S (O) 2nR nr o, C wherein 1-6-alkyl is optionally selected from following substituting group and replaces by one or more: CN, halogen, hydroxyl, C 1-6-alkoxyl group, Heterocyclylalkyl, cycloalkyl, aryl, heteroaryl ,-NH 2,-NHC 1-6-alkyl and-N (C 1-6-alkyl) 2, wherein aryl, C 3-8cycloalkyl, heteroaryl and Heterocyclylalkyl, separately or as the part of another part, optionally by one, two or three replace independently selected from following substituting group: CN, halogen and C 1-6alkyl.In another embodiment of formula (II), R 5heterocyclylalkyl is piperazinyl, Diazesuberane base, piperidyl, pyrrolidyl, morpholinyl, hexahydropyrrolo also [1, 2-a] pyrazinyl, oxo piperazinyl, (1S, 4S)-2, 5-diazabicyclo [2.2.1] heptan-2-base, (1R, 4R)-2, 5-diazabicyclo [2.2.1] heptan-2-base, 6-oxo-1, 4, 5, 6-tetrahydro pyridazine-3-base, octahydro-2H-quinolizinyl, 3, 7-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-3-base, (8aR)-hexahydropyrrolo also [1, 2-a] pyrazine-2 (1H)-Ji, octahydro-2H-pyrido [1, 2-a] pyrazine-2-base, thiazolidine-2-Ji, 4-oxo-1, 3-thiazolidine-2-Ji, (3R)-1-azabicyclo [2.2.2] oct-3-yl or thio-morpholinyl.
In another embodiment of formula (II), R 4be
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。
R wherein 5halogen, C 1-6-alkyl, C 1-6haloalkyl or OR g; P is 0 or 1; R 7cN, NO 2, halogen, C 1-6-alkyl, C 1-6-haloalkyl, OR m, SR m, C (O) R m, C (O) NR nr o, C (O) OR m, NR nr o, NR nc (O) R m, S (O) 2r m, NR ns (O) 2r mor S (O) 2nR mr o; Q is 0 or 1.
In an embodiment of formula (II), R 3be phenyl, wherein phenyl is selected from following substituting group by one and replaces: C 1-6-alkyl, C 1-6-haloalkyl, halogen and OR d;
R 4be ; R 5halogen, C 1-6alkyl, C 1-6haloalkyl or OR g; P is 0 or 1.
In an embodiment of formula (II), R 4be
Figure DEST_PATH_IMAGE031
R wherein 5halogen, C 1-6alkyl, C 1-6haloalkyl or OR g; R gbe selected from H, C 1-6alkyl, aryl, C 3-8cycloalkyl, heteroaryl and Heterocyclylalkyl; C wherein 1-6-alkyl is optionally selected from following substituting group and replaces by one or more: CN, halogen, hydroxyl, C 1-6-alkoxyl group, Heterocyclylalkyl ,-NH 2,-NHC 1-6-alkyl and-N (C 1-6-alkyl) 2, wherein aryl, C 3-8cycloalkyl, heteroaryl or Heterocyclylalkyl, separately or as the part of another part, be optionally selected from following substituting group and replace by one or more: halogen, C 1-6-alkyl, C 1-6-haloalkyl, C 1-6-hydroxyalkyl, hydroxyl, oxo, C 1-6-alkoxyl group, C 1-6-halogenated alkoxy ,-C (O) C 1-6-alkyl ,-S (O) 2c 1-6-alkyl ,-NH 2,-NH (C 1-6-alkyl) ,-N (C 1-6-alkyl) 2with-N (C 1-6-alkyl) (C 3-8-cycloalkyl); R hand R iwhen occurring at every turn independently selected from H, C 1-6alkyl, aryl, C 3-8cycloalkyl, heteroaryl and Heterocyclylalkyl; C wherein 1-6-alkyl is optionally selected from following substituting group and replaces by one or more: CN, halogen, hydroxyl, C 1-6-alkoxyl group, Heterocyclylalkyl ,-NH 2,-NHC 1-6-alkyl and-N (C 1-6-alkyl) 2, wherein aryl, C 3-8cycloalkyl, heteroaryl or Heterocyclylalkyl, separately or as the part of another part, be optionally selected from following substituting group and replace by one or more: halogen, C 1-6-alkyl, C 1-6-haloalkyl, C 1-6-hydroxyalkyl, hydroxyl, oxo, C 1-6-alkoxyl group, C 1-6-halogenated alkoxy, C (O) C 1-6-alkyl, S (O) 2c 1-6-alkyl ,-NH 2,-NH (C 1-6-alkyl) ,-N (C 1-6-alkyl) 2with-N (C 1-6-alkyl) (C 3-8-cycloalkyl); P is 0,1 or 2.
In an embodiment of formula (II), R 4be 5-16 unit monocycle, dicyclo or tricyclic heterocyclic base, wherein heterocyclic radical is optionally by one or more R 6replace R 6cN, NO 2, halogen, C 3-8cycloalkyl, OR j, SR j, C (O) R j, C (O) NR kr l, C (O) OR j, NR kr l, NR kc (O) R j, S (O) 2r j, NR ks (O) 2r jor S (O) 2nR kr l, C wherein 1-6-alkyl is optionally selected from following substituting group and replaces by one or more: CN, halogen, hydroxyl, C 1-6-alkoxyl group, Heterocyclylalkyl, cycloalkyl, heteroaryl, aryl ,-NH 2,-NHC 1-6-alkyl and-N (C 1-6-alkyl) 2; Wherein Heterocyclylalkyl, cycloalkyl, heteroaryl, aryl, separately or as the part of another part, optionally by one, two or three replace independently selected from following substituting group: CN, halogen, heteroaryl, benzyl and C 1-6alkyl.
In an embodiment of formula (II), R 4it is 4-8 unit monocyclic heterocycles base.In another embodiment, R 44-8 unit's Heterocyclylalkyl or heterocycloalkenyl.In another embodiment, R 4it is 5-7 unit heteroaryl.In another embodiment of formula (II), R 4pyrrolidyl, tetrahydrofuran base, tetrahydro-thienyl, imidazolidyl, pyrazolidyl, piperidyl, diaza
Figure 666104DEST_PATH_IMAGE002
base, THP trtrahydropyranyl, piperazinyl, alkyl dioxin, thiazolidine-2-Ji, morpholinyl, 2-oxo-pyrrolidine base, 4-oxo-1,3-thiazoles alkane-2-base, thio-morpholinyl, 2,5-dioxo pyrrolidyl, 2-oxo-piperidine base, 4-oxo-piperidine base or 2,6-dioxopiperidine base.In another embodiment of formula (I), R 4pyridyl (pyridyl), pyrazinyl (pyrazyl), pyridyl (pyridinyl), pyrimidyl, pyridazinyl, 1,3,5-, 1,2,4-or 1,2,3-triazinyl, imidazolyl, furyl, thienyl, pyrazolyl ， oxazolyl ， isoxazolyl, thiazolyl, 1,2,3-, 1,2,4-, 1,2,5-or 1,3,4-oxadiazolyl, or isothiazolyl.In one embodiment, R 4unsubstituted.In another embodiment, R 4by one, two or three R 6replace R 6halogen, C 1-6-alkyl, C 1-6-haloalkyl, OR j, C (O) R j, NR kr lor S (O) 2r j.
In an embodiment of formula (II), R 4it is 7-11 unit bicyclic heterocyclic radical.In another embodiment, R 47-11 unit's bicyclic heterocycle alkyl or bicyclic heterocycle thiazolinyl.In another embodiment, R 4it is 7-11 unit bicyclic heteroaryl.In another embodiment, R 42, 3-dihydro-2-oxo--1H-indyl, hexahydropyrrolo also [1, 2-a] pyrazinyl, (1R, 4R)-2, 5-diazabicyclo [2.2.1] heptan-2-base, benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolyl, quinolyl-N-oxide compound, tetrahydro isoquinolyl, isoquinolyl, benzimidazolyl-, benzopyranyl, indolizinyl, benzofuryl, chromone base, tonka bean camphor base, scold Lin Ji, quinoxalinyl, indazolyl, pyrrolopyridinyl, furo pyridyl, dihydro-iso indolyl, dihydroquinazoline base, 3, 4-dihydro-4-oxo-quinazolyl, 6-oxo-1, 4, 5, 6-tetrahydro pyridazine-3-base, octahydro-2H-quinolizinyl, 3, 7-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-3-base, (8aR)-hexahydropyrrolo also [1, 2-a] pyrazine-2 (1H)-Ji, benzisothiazole base, benzoisoxazole base, benzo two azine groups, benzofuraxan base, benzo thiapyran base, octahydro-2H-pyrido [1, 2-a] pyrazine-2-base, benzotriazole base, phenylpyrazole base, 1, 3-benzodioxole base, (3R)-1-azabicyclo [2.2.2] oct-3-yl, dihydro benzo furyl, dihydrobenzo thienyl, thiochroman base, thiochroman base sulfone, dihydrobenzopyrans base, Er hydrogen benzoxazinyl, 3-oxo-3, 4-dihydro-1, 4-benzoxazinyl, indolinyl, indazolyl, 4-oxo-1, 4-dihydro cinnolines-6-base, isochroman base, isoindolinyl, naphthyridinyl, phthalazinyl, piperonyl, purine radicals, pyridopyridine base, pyrrolotriazine base, quinazolyl, 1, 2, 3-diazosulfide base-5-base, 1, 3-benzothiazol-6-yl, tetrahydric quinoline group, thienofuran base, thienopyridine base, [1, 2-a] pyridine-2-base, 2, 3-glyoxalidine also [2, 1-b] [1, 3] thiazole-6-base, imidazo [2, 1-b] [1, 3] thiazole-6-base, 3-oxo-2, 3-dihydro-1H-indazole-7-base, 5, 6, 7, 8-tetrahydrochysene-1, 6-naphthyridines-3-base, 2, 7-diaza spiro [3.5] ninth of the ten Heavenly Stems-7-base, 2, 6-diaza spiro [3.3] heptan-2-base, 2, 6-diaza spiro [3.4] is pungent-2-base, 2, 7-diaza spiro [3.5] ninth of the ten Heavenly Stems-2-base, 3, 0-diaza spiro [5.5] 10 one-3-bases, (3aR, 6aR)-hexahydropyrrolo also [3, 4-b] pyrroles-1 (2H)-Ji, 2, 3, 4, 5-tetrahydrochysene-1H-2-benzo-aza base, 2,3,4,5-tetrahydrochysene-1H-3-benzo-aza
Figure 388389DEST_PATH_IMAGE002
base, 1,2,3,4-tetrahydroisoquinoline-7-base, 1,2,3,4-tetrahydric quinoline group, 4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-base, 2,3-dihydro-1H-indoles-5-base, indolinyl, 2,3-dihydro-1H-indazolyl, isoindolinyl, 1,2,3,4-tetrahydroisoquinoline-6-base or thienothiophene base.In an embodiment of formula (I), R 4unsubstituted.In another embodiment of formula (II), R 4by one, two or three R 6replace R 6cN, NO 2, halogen, C 3-8cycloalkyl, OR j, SR j, C (O) R j, C (O) NR kr l, C (O) OR j, NR kr l, NR kc (O) R j, S (O) 2r j, NR ks (O) 2r jor S (O) 2nR kr l, C wherein 1-6-alkyl is optionally selected from following substituting group and replaces by one or more: CN, halogen, hydroxyl, C 1-6-alkoxyl group, Heterocyclylalkyl, cycloalkyl, heteroaryl, aryl ,-NH 2,-NHC 1-6-alkyl and-N (C 1-6-alkyl) 2; Wherein Heterocyclylalkyl, cycloalkyl, heteroaryl, aryl, separately or as the part of another part, optionally by one, two or three replace independently selected from following substituting group: CN, halogen, heteroaryl, benzyl and C 1-6alkyl.
In an embodiment of formula (II), R 4be
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Figure 879227DEST_PATH_IMAGE016
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Figure 834731DEST_PATH_IMAGE018
Figure 948181DEST_PATH_IMAGE032
or
Figure 187925DEST_PATH_IMAGE020
。
In an embodiment of formula (II), R 4it is 10-15 unit tricyclic heterocyclic base.In another embodiment, R 410-15 unit's tricyclic heterocyclic alkyl or tricyclic heterocyclic thiazolinyl.In another embodiment, R 4it is 10-15 unit tricyclic heteroaryl.In an embodiment of formula (II), R 4be 5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base or 2' also, 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-base.In an embodiment of formula (II), R 4unsubstituted.In another embodiment of formula (II), R 4by one, two or three R 6replace R 6halogen, C 1-6-alkyl, C 1-6-haloalkyl, OR j, C (O) R j, NR kr lor S (O) 2r j.
In an embodiment of formula (II), R 4be
Figure DEST_PATH_IMAGE033
。
In one embodiment, the present invention partly relates to the compounds category with formula (IIa) structure
Figure 412233DEST_PATH_IMAGE034
R wherein 4described in formula (II), R qand R phalogen or hydrogen independently.
the embodiment of formula (III)
In one embodiment, the present invention partly relates to the compounds category with formula (III) structure
R wherein 1, R 2, R 3and R 4described in formula (I).
In an embodiment of formula (III), R 2h.In another embodiment of formula (III), R 2c 1-6alkyl.
In an embodiment of formula (III), R 3be aryl, wherein aryl is optionally selected from following substituting group and replaces by one or more: C 1-6-alkyl, C 1-6-haloalkyl, C 2-6-thiazolinyl, Heterocyclylalkyl, aryl, heteroaryl, halogen, oxo, cyano group, nitro ,-OR d,-C (O) R d,-C (O) OR d,-OC (O) R d,-SR d,-S (O) R d,-SO 2r d,-NR er f,-NHC (O) R e,-NHC (O) NHR e,-NHC (O) OR e,-NHSO 2r d,-C (O) NHR ewith-SO 2nHNR e.In another embodiment of formula (III), R 3be aryl, wherein aryl is selected from phenyl, naphthyl, indenyl, indanyl and tetralyl.In another embodiment of formula (III), R 3it is phenyl.In another embodiment of formula (III), R 3be phenyl, it is optionally selected from following substituting group and replaces by one or more: halogen, C 1-6alkyl, C 1-6haloalkyl ,-OC 1-6alkyl or-OC 1-6haloalkyl.In another embodiment of formula (III), R 3by one, be selected from the phenyl that following substituting group replaces: halogen, C 1-6alkyl, C 1-6haloalkyl ,-OC 1-6alkyl and-OC 1-6haloalkyl.In another embodiment of formula (III), R 3be
Figure 536047DEST_PATH_IMAGE036
, R wherein pbe selected from halogen, C 1-6alkyl, C 1-6haloalkyl ,-OC 1-6alkyl and-OC 1-6haloalkyl.In another embodiment of formula (III), R pit is halogen.In another embodiment of formula (III), R pit is halogen.In another embodiment of formula (I), R 3be
Figure DEST_PATH_IMAGE037
, R wherein pand R qindependently selected from: halogen, C 1-6alkyl, C 1-6haloalkyl ,-OC 1-6alkyl or-OC 1-6haloalkyl.In another embodiment of formula (III), R pand R qit is all halogen.
In an embodiment of formula (III), R 4phenyl, naphthyl, tetralyl, indenyl or indanyl, wherein phenyl, naphthyl, tetralyl, indenyl or indanyl are optionally by one or more R 5replace; And CN, NO 2, halogen, C 1-6-alkyl, OR g, SR g, C (O) R g, C (O) NR hr i, C (O) OR g, NR hr i, NR hc (O) R g, S (O) 2r g, NR hs (O) 2r g, S (O) 2nR hr i, aryl, cycloalkyl, heteroaryl, Heterocyclylalkyl or heterocycloalkenyl, wherein C 1-6-alkyl is optionally selected from following substituting group and replaces by one or more: CN, halogen, hydroxyl, S (O) 2nH (C 1-6-alkyl), C 1-6-alkoxyl group, Heterocyclylalkyl, cycloalkyl, heteroaryl, aryl ,-NH 2,-NHC 1-6-alkyl and-N (C 1-6-alkyl) 2; Wherein aryl, cycloalkyl, heteroaryl or Heterocyclylalkyl, separately or as the part of another part, optionally by one, two or three R 7replace; R wherein 7cN, NO 2, halogen, oxo, C 1-6alkyl, aryl, C 3-8cycloalkyl, heteroaryl, Heterocyclylalkyl, OR m, SR m, C (O) R m, C (O) NR nr o, C (O) OR m, OC (O) R m, OC (O) NR nr o, NR nr o, NR nc (O) R m, S (O) R m, S (O) NR nr o, S (O) 2r m, NR ns (O) 2r mor S (O) 2nR nr o, C wherein 1-6-alkyl is optionally selected from following substituting group and replaces by one or more: CN, halogen, hydroxyl, C 1-6-alkoxyl group, Heterocyclylalkyl, cycloalkyl, aryl, heteroaryl ,-NH 2,-NHC 1-6-alkyl and-N (C 1-6-alkyl) 2, wherein aryl, C 3-8cycloalkyl, heteroaryl and Heterocyclylalkyl, separately or as the part of another part, optionally by one, two or three replace independently selected from following substituting group: CN, halogen and C 1-6alkyl.In another embodiment of formula (III), R 4naphthyl, tetralyl, indenyl or indanyl, wherein naphthyl, tetralyl, indenyl or indanyl are unsubstituted.In another embodiment of formula (III), R 4naphthyl, tetralyl, indenyl or indanyl, wherein naphthyl, tetralyl, indenyl or indanyl by one, two or three are selected from following substituting group and replace: CN, NO 2, halogen, C 1-6-alkyl, C 1-6-haloalkyl, OR g, SR g, C (O) R g, C (O) NR hr i, C (O) OR g, NR hr i, NR hc (O) R g, S (O) 2r g, NR hs (O) 2r gand S (O) 2nR hr i.
In an embodiment of formula (III), R 4it is phenyl.In another embodiment of formula (III), R 4be phenyl, wherein phenyl is unsubstituted.In another embodiment of formula (III), R 4be phenyl, wherein phenyl is by one, two or three R 5replace R 5cN, NO 2, halogen, C 1-6-alkyl, OR g, SR g, C (O) R g, C (O) NR hr i, C (O) OR g, NR hr i, NR hc (O) R g, S (O) 2r g, NR hs (O) 2r g, S (O) 2nR hr i, aryl, cycloalkyl, heteroaryl, Heterocyclylalkyl or heterocycloalkenyl, wherein C 1-6-alkyl is optionally selected from following substituting group and replaces by one or more: CN, halogen, hydroxyl, S (O) 2nH (C 1-6-alkyl), C 1-6-alkoxyl group, Heterocyclylalkyl, cycloalkyl, heteroaryl, aryl, NH 2, NHC 1-6-alkyl and-N (C 1-6-alkyl) 2; Wherein aryl, cycloalkyl, heteroaryl or Heterocyclylalkyl, separately or as the part of another part, optionally by one, two or three R 7replace; R wherein 7cN, NO 2, halogen, oxo, C 1-6alkyl, aryl, C 3-8cycloalkyl, heteroaryl, Heterocyclylalkyl, OR m, SR m, C (O) R m, C (O) NR nr o, C (O) OR m, OC (O) R m, OC (O) NR nr o, NR nr o, NR nc (O) R m, S (O) R m, S (O) NR nr o, S (O) 2r m, NR ns (O) 2r mor S (O) 2nR nr o, C wherein 1-6-alkyl is optionally selected from following substituting group and replaces by one or more: CN, halogen, hydroxyl, C 1-6-alkoxyl group, Heterocyclylalkyl, cycloalkyl, aryl, heteroaryl ,-NH 2,-NHC 1-6-alkyl and-N (C 1-6-alkyl) 2, wherein aryl, C 3-8cycloalkyl, heteroaryl and Heterocyclylalkyl, separately or as the part of another part, optionally by one, two or three replace independently selected from following substituting group: CN, halogen and C 1-6alkyl.In another embodiment of formula (II), R 7c 1-6-alkyl, C 1-6haloalkyl, or C (O) R m; R mc 1-6alkyl, C 1-6haloalkyl or C 3-8cycloalkyl.
In an embodiment of formula (III), R 4be phenyl, wherein phenyl is by Heterocyclylalkyl and optional one or two R 5replace, wherein R 5halogen, C 1-6alkyl, C 1-6haloalkyl or OR g, wherein Heterocyclylalkyl is optionally by one, two or three R 7replace; R wherein 7cN, NO 2, halogen, oxo, C 1-6alkyl, aryl, C 3-8cycloalkyl, heteroaryl, Heterocyclylalkyl, OR m, SR m, C (O) R m, C (O) NR nr o, C (O) OR m, OC (O) R m, OC (O) NR nr o, NR nr o, NR nc (O) R m, S (O) R m, S (O) NR nr o, S (O) 2r m, NR ns (O) 2r mor S (O) 2nR nr o, C wherein 1-6-alkyl is optionally selected from following substituting group and replaces by one or more: CN, halogen, hydroxyl, C 1-6-alkoxyl group, Heterocyclylalkyl, cycloalkyl, aryl, heteroaryl ,-NH 2,-NHC 1-6-alkyl and-N (C 1-6-alkyl) 2, wherein aryl, C 3-8cycloalkyl, heteroaryl and Heterocyclylalkyl, separately or as the part of another part, optionally by one, two or three replace independently selected from following substituting group: CN, halogen and C 1-6alkyl.In another embodiment of formula (III), R 5heterocyclylalkyl is piperazinyl, Diazesuberane base, piperidyl, pyrrolidyl, morpholinyl, hexahydropyrrolo also [1, 2-a] pyrazinyl, oxo piperazinyl, (1S, 4S)-2, 5-diazabicyclo [2.2.1] heptan-2-base, (1R, 4R)-2, 5-diazabicyclo [2.2.1] heptan-2-base, 6-oxo-1, 4, 5, 6-tetrahydro pyridazine-3-base, octahydro-2H-quinolizinyl, 3, 7-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-3-base, (8aR)-hexahydropyrrolo also [1, 2-a] pyrazine-2 (1H)-Ji, octahydro-2H-pyrido [1, 2-a] pyrazine-2-base, thiazolidine-2-Ji, 4-oxo-1, 3-thiazolidine-2-Ji, (3R)-1-azabicyclo [2.2.2] oct-3-yl or thio-morpholinyl.
In another embodiment of formula (III), R 4be
Figure 633447DEST_PATH_IMAGE038
Figure 136290DEST_PATH_IMAGE008
Figure 317872DEST_PATH_IMAGE009
Figure DEST_PATH_IMAGE039
。
R wherein 5halogen, C 1-6-alkyl, C 1-6haloalkyl or OR g; P is 0 or 1; R 7cN, NO 2, halogen, C 1-6-alkyl, C 1-6-haloalkyl, OR m, SR m, C (O) R m, C (O) NR nr o, C (O) OR m, NR nr o, NR nc (O) R m, S (O) 2r m, NR ns (O) 2r mor S (O) 2nR mr o; Q is 0 or 1.
In an embodiment of formula (III), R 3be phenyl, wherein phenyl is selected from following substituting group by one and replaces: C 1-6-alkyl, C 1-6-haloalkyl, halogen and OR d;
R 4be
Figure 819130DEST_PATH_IMAGE030
; R 5halogen, C 1-6alkyl, C 1-6haloalkyl or OR g; P is 0 or 1.
In an embodiment of formula (III), R 4be
Figure 46849DEST_PATH_IMAGE040
R wherein 5halogen, C 1-6alkyl, C 1-6haloalkyl or OR g; R gbe selected from H, C 1-6alkyl, aryl, C 3-8cycloalkyl, heteroaryl and Heterocyclylalkyl; C wherein 1-6-alkyl is optionally selected from following substituting group and replaces by one or more: CN, halogen, hydroxyl, C 1-6-alkoxyl group, Heterocyclylalkyl ,-NH 2,-NHC 1-6-alkyl and-N (C 1-6-alkyl) 2, wherein aryl, C 3-8cycloalkyl, heteroaryl or Heterocyclylalkyl, separately or as the part of another part, be optionally selected from following substituting group and replace by one or more: halogen, C 1-6-alkyl, C 1-6-haloalkyl, C 1-6-hydroxyalkyl, hydroxyl, oxo, C 1-6-alkoxyl group, C 1-6-halogenated alkoxy, C (O) C 1-6-alkyl, S (O) 2c 1-6-alkyl ,-NH 2,-NH (C 1-6-alkyl) ,-N (C 1-6-alkyl) 2with-N (C 1-6-alkyl) (C 3-8-cycloalkyl); R hand R iwhen occurring at every turn independently selected from H, C 1-6alkyl, aryl, C 3-8cycloalkyl, heteroaryl and Heterocyclylalkyl; C wherein 1-6-alkyl is optionally selected from following substituting group and replaces by one or more: CN, halogen, hydroxyl, C 1-6-alkoxyl group, Heterocyclylalkyl ,-NH 2,-NHC 1-6-alkyl and-N (C 1-6-alkyl) 2, wherein aryl, C 3-8cycloalkyl, heteroaryl or Heterocyclylalkyl, separately or as the part of another part, be optionally selected from following substituting group and replace by one or more: halogen, C 1-6-alkyl, C 1-6-haloalkyl, C 1-6-hydroxyalkyl, hydroxyl, oxo, C 1-6-alkoxyl group, C 1-6-halogenated alkoxy, C (O) C 1-6-alkyl, S (O) 2c 1-6-alkyl ,-NH 2,-NH (C 1-6-alkyl) ,-N (C 1-6-alkyl) 2with-N (C 1-6-alkyl) (C 3-8-cycloalkyl); P is 0,1 or 2.
In an embodiment of formula (III), R 4be 5-16 unit monocycle, dicyclo or tricyclic heterocyclic base, wherein heterocyclic radical is optionally by one or more R 6replace R 6cN, NO 2, halogen, C 3-8cycloalkyl, OR j, SR j, C (O) R j, C (O) NR kr l, C (O) OR j, NR kr l, NR kc (O) R j, S (O) 2r j, NR ks (O) 2r jor S (O) 2nR kr l, C wherein 1-6-alkyl is optionally selected from following substituting group and replaces by one or more: CN, halogen, hydroxyl, C 1-6-alkoxyl group, Heterocyclylalkyl, cycloalkyl, heteroaryl, aryl ,-NH 2,-NHC 1-6-alkyl and-N (C 1-6-alkyl) 2; Wherein Heterocyclylalkyl, cycloalkyl, heteroaryl, aryl, separately or as the part of another part, optionally by one, two or three replace independently selected from following substituting group: CN, halogen, heteroaryl, benzyl and C 1-6alkyl.
In an embodiment of formula (III), R 4it is 4-8 unit monocyclic heterocycles base.In another embodiment, R 44-8 unit's Heterocyclylalkyl or heterocycloalkenyl.In another embodiment, R 4it is 5-7 unit heteroaryl.In another embodiment of formula (III), R 4pyrrolidyl, tetrahydrofuran base, tetrahydro-thienyl, imidazolidyl, pyrazolidyl, piperidyl, Diazesuberane base, THP trtrahydropyranyl, piperazinyl, alkyl dioxin, thiazolidine-2-Ji, morpholinyl, 2-oxo-pyrrolidine base, 4-oxo-1,3-thiazoles alkane-2-base, thio-morpholinyl, 2,5-dioxo pyrrolidyl, 2-oxo-piperidine base, 4-oxo-piperidine base or 2,6-dioxopiperidine base.In another embodiment of formula (I), R 4pyridyl (pyridyl), pyrazinyl (pyrazyl), pyridyl (pyridinyl), pyrimidyl, pyridazinyl, 1,3,5-, 1,2,4-or 1,2,3-triazinyl, imidazolyl, furyl, thienyl, pyrazolyl ， oxazolyl ， isoxazolyl, thiazolyl, 1,2,3-, 1,2,4-, 1,2,5-or 1,3,4-oxadiazolyl, or isothiazolyl.In one embodiment, R 4unsubstituted.In another embodiment, R 4by one, two or three R 6replace R 6halogen, C 1-6-alkyl, C 1-6-haloalkyl, OR j, C (O) R j, NR kr lor S (O) 2r j.
In an embodiment of formula (III), R 4it is 7-11 unit bicyclic heterocyclic radical.In another embodiment, R 47-11 unit's bicyclic heterocycle alkyl or bicyclic heterocycle thiazolinyl.In another embodiment, R 4it is 7-11 unit bicyclic heteroaryl.In another embodiment, R 42, 3-dihydro-2-oxo--1H-indyl, hexahydropyrrolo also [1, 2-a] pyrazinyl, (1R, 4R)-2, 5-diazabicyclo [2.2.1] heptan-2-base, benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolyl, quinolyl-N-oxide compound, tetrahydro isoquinolyl, isoquinolyl, benzimidazolyl-, benzopyranyl, indolizinyl, benzofuryl, chromone base, tonka bean camphor base, scold Lin Ji, quinoxalinyl, indazolyl, pyrrolopyridinyl, furo pyridyl, dihydro-iso indolyl, dihydroquinazoline base, 3, 4-dihydro-4-oxo-quinazolyl, 6-oxo-1, 4, 5, 6-tetrahydro pyridazine-3-base, octahydro-2H-quinolizinyl, 3, 7-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-3-base, (8aR)-hexahydropyrrolo also [1, 2-a] pyrazine-2 (1H)-Ji, benzisothiazole base, benzoisoxazole base, benzo two azine groups, benzofuraxan base, benzo thiapyran base, octahydro-2H-pyrido [1, 2-a] pyrazine-2-base, benzotriazole base, phenylpyrazole base, 1, 3-benzodioxole base, (3R)-1-azabicyclo [2.2.2] oct-3-yl, dihydro benzo furyl, dihydrobenzo thienyl, thiochroman base, thiochroman base sulfone, dihydrobenzopyrans base, Er hydrogen benzoxazinyl, 3-oxo-3, 4-dihydro-1, 4-benzoxazinyl, indolinyl, indazolyl, 4-oxo-1, 4-dihydro cinnolines-6-base, isochroman base, isoindolinyl, naphthyridinyl, phthalazinyl, piperonyl, purine radicals, pyridopyridine base, pyrrolotriazine base, quinazolyl, 1, 2, 3-diazosulfide-5-base, 1, 3-benzothiazol-6-yl, tetrahydric quinoline group, thienofuran base, thienopyridine base, [1, 2-a] pyridine-2-base, 2, 3-glyoxalidine also [2, 1-b] [1, 3] thiazole-6-base, imidazo [2, 1-b] [1, 3] thiazole-6-base, 3-oxo-2, 3-dihydro-1H-indazole-7-base, 5, 6, 7, 8-tetrahydrochysene-1, 6-naphthyridines-3-base, 2, 7-diaza spiro [3.5] ninth of the ten Heavenly Stems-7-base, 2, 6-diaza spiro [3.3] heptan-2-base, 2, 6-diaza spiro [3.4] is pungent-2-base, 2, 7-diaza spiro [3.5] ninth of the ten Heavenly Stems-2-base, 3, 0-diaza spiro [5.5] 10 one-3-bases, (3aR, 6aR)-hexahydropyrrolo also [3, 4-b] pyrroles-1 (2H)-Ji, 2, 3, 4, 5-tetrahydrochysene-1H-2-benzo-aza
Figure 612959DEST_PATH_IMAGE002
base, 2,3,4,5-tetrahydrochysene-1H-3-benzo-aza
Figure 462098DEST_PATH_IMAGE002
base, 1,2,3,4-tetrahydroisoquinoline-7-base, 1,2,3,4-tetrahydric quinoline group, 4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-base, 2,3-dihydro-1H-indoles-5-base, indolinyl, 2,3-dihydro-1H-indazolyl, isoindolinyl, 1,2,3,4-tetrahydroisoquinoline-6-base or thienothiophene base.In an embodiment of formula (I), R 4unsubstituted.In another embodiment of formula (II), R 4by one, two or three R 6replace R 6cN, NO 2, halogen, C 3-8cycloalkyl, OR j, SR j, C (O) R j, C (O) NR kr l, C (O) OR j, NR kr l, NR kc (O) R j, S (O) 2r j, NR ks (O) 2r jor S (O) 2nR kr l, C wherein 1-6-alkyl is optionally selected from following substituting group and replaces by one or more: CN, halogen, hydroxyl, C 1-6-alkoxyl group, Heterocyclylalkyl, cycloalkyl, heteroaryl, aryl ,-NH 2,-NHC 1-6-alkyl and-N (C 1-6-alkyl) 2; Wherein Heterocyclylalkyl, cycloalkyl, heteroaryl, aryl, separately or as the part of another part, optionally by one, two or three replace independently selected from following substituting group: CN, halogen, heteroaryl, benzyl and C 1-6alkyl.
In an embodiment of formula (III), R 4be
Figure 822672DEST_PATH_IMAGE013
Figure 272108DEST_PATH_IMAGE014
Figure 532505DEST_PATH_IMAGE016
Figure 638214DEST_PATH_IMAGE017
Figure 309367DEST_PATH_IMAGE018
Figure 482860DEST_PATH_IMAGE019
or
Figure 493541DEST_PATH_IMAGE020
。
In an embodiment of formula (III), R 4it is 10-15 unit tricyclic heterocyclic base.In another embodiment, R 410-15 unit's tricyclic heterocyclic alkyl or tricyclic heterocyclic thiazolinyl.In another embodiment, R 4it is 10-15 unit tricyclic heteroaryl.In an embodiment of formula (III), R 4be 5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base or 2' also, 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-base.In an embodiment of formula (III), R 4unsubstituted.In another embodiment of formula (III), R 4by one, two or three R 6replace R 6halogen, C 1-6-alkyl, C 1-6-haloalkyl, OR j, C (O) R j, NR kr lor S (O) 2r j.
In an embodiment of formula (III), R 4be
Figure DEST_PATH_IMAGE041
。
In one embodiment, the present invention partly relates to the compounds category with formula (IIIa) structure
Figure 274546DEST_PATH_IMAGE042
R wherein 4described in formula (III), R pand R qhalogen or hydrogen independently.
the embodiment of formula (IV)
In one embodiment, the present invention partly relates to the compounds category with formula (IV) structure
Figure DEST_PATH_IMAGE043
R wherein 1, R 2, R 3and R 4described in formula (I).
In an embodiment of formula (IV), R 3be aryl, wherein aryl is optionally selected from following substituting group and replaces by one or more :-C 1-6-alkyl ,-C 1-6-haloalkyl, C 2-6-thiazolinyl, Heterocyclylalkyl, aryl, heteroaryl, halogen, oxo, cyano group, nitro ,-OR d,-C (O) R d,-C (O) OR d,-OC (O) R d,-SR d,-S (O) R d,-SO 2r d,-NR er f,-NHC (O) R e,-NHC (O) NHR e,-NHC (O) OR e,-NHSO 2r d,-C (O) NHR ewith-SO 2nHNR e.In another embodiment of formula (IV), R 3be aryl, wherein aryl is selected from phenyl, naphthyl, indenyl, indanyl and tetralyl.In another embodiment of formula (IV), R 3it is phenyl.In another embodiment of formula (IV), R 3be phenyl, it is optionally selected from following substituting group and replaces by one or more: halogen, C 1-6alkyl, C 1-6haloalkyl ,-OC 1-6alkyl and-OC 1-6haloalkyl.In another embodiment of formula (IV), R 3by one, be selected from the phenyl that following substituting group replaces: halogen, C 1-6alkyl, C 1-6haloalkyl ,-OC 1-6alkyl and-OC 1-6haloalkyl.In another embodiment of formula (IV), R 3be
Figure 432995DEST_PATH_IMAGE036
, R wherein pbe selected from halogen, C 1-6alkyl, C 1-6haloalkyl ,-OC 1-6alkyl and-OC 1-6haloalkyl.In another embodiment of formula (IV), R pit is halogen.In another embodiment of formula (IV), R pit is halogen.In another embodiment of formula (IV), R pit is halogen.In another embodiment of formula (IV), R 3be , R wherein pand R qindependently selected from halogen, C 1-6alkyl, C 1-6haloalkyl ,-OC 1-6alkyl or-OC 1-6haloalkyl.In another embodiment of formula (IV), R pand R qit is all halogen.
In an embodiment of formula (IV), R 4phenyl, naphthyl, tetralyl, indenyl, or indanyl, wherein phenyl, naphthyl, tetralyl, indenyl or indanyl are optionally by one or more R 5replace; And CN, NO 2, halogen, C 1-6-alkyl, OR g, SR g, C (O) R g, C (O) NR hr i, C (O) OR g, NR hr i, NR hc (O) R g, S (O) 2r g, NR hs (O) 2r g, S (O) 2nR hr i, aryl, cycloalkyl, heteroaryl, Heterocyclylalkyl or heterocycloalkenyl, wherein C 1-6-alkyl is optionally selected from following substituting group and replaces by one or more: CN, halogen, hydroxyl, S (O) 2nH (C 1-6-alkyl), C 1-6-alkoxyl group, Heterocyclylalkyl, cycloalkyl, heteroaryl, aryl ,-NH 2,-NHC 1-6-alkyl and-N (C 1-6-alkyl) 2; Wherein aryl, cycloalkyl, heteroaryl or Heterocyclylalkyl, separately or as the part of another part, optionally by one, two or three R 7replace; R wherein 7cN, NO 2, halogen, oxo, C 1-6alkyl, aryl, C 3-8cycloalkyl, heteroaryl, Heterocyclylalkyl, OR m, SR m, C (O) R m, C (O) NR nr o, C (O) OR m, OC (O) R m, OC (O) NR nr o, NR nr o, NR nc (O) R m, S (O) R m, S (O) NR nr o, S (O) 2r m, NR ns (O) 2r mor S (O) 2nR nr o, C wherein 1-6-alkyl is optionally selected from following substituting group and replaces by one or more: CN, halogen, hydroxyl, C 1-6-alkoxyl group, Heterocyclylalkyl, cycloalkyl, aryl, heteroaryl ,-NH 2,-NHC 1-6-alkyl and-N (C 1-6-alkyl) 2, wherein aryl, C 3-8cycloalkyl, heteroaryl and Heterocyclylalkyl, separately or as the part of another part, optionally by one, two or three replace independently selected from following substituting group: CN, halogen and C 1-6alkyl.In another embodiment of formula (IV), R 4naphthyl, tetralyl, indenyl or indanyl, wherein naphthyl, tetralyl, indenyl or indanyl are unsubstituted.In another embodiment of formula (IV), R 4naphthyl, tetralyl, indenyl or indanyl, wherein naphthyl, tetralyl, indenyl or indanyl by one, two or three are selected from following substituting group and replace: CN, NO 2, halogen, C 1-6-alkyl, C 1-6-haloalkyl, OR g, SR g, C (O) R g, C (O) NR hr i, C (O) OR g, NR hr i, NR hc (O) R g, S (O) 2r g, NR hs (O) 2r gand S (O) 2nR hr i.
In an embodiment of formula (IV), R 4it is phenyl.In another embodiment of formula (IV), R 4be phenyl, wherein phenyl is unsubstituted.In another embodiment of formula (IV), R 4be phenyl, wherein phenyl is by one, two or three R 5replace R 5cN, NO 2, halogen, C 1-6-alkyl, OR g, SR g, C (O) R g, C (O) NR hr i, C (O) OR g, NR hr i, NR hc (O) R g, S (O) 2r g, NR hs (O) 2r g, S (O) 2nR hr i, aryl, cycloalkyl, heteroaryl, Heterocyclylalkyl or heterocycloalkenyl, wherein C 1-6-alkyl is optionally selected from following substituting group and replaces by one or more: CN, halogen, hydroxyl, S (O) 2nH (C 1-6-alkyl), C 1-6-alkoxyl group, Heterocyclylalkyl, cycloalkyl, heteroaryl, aryl ,-NH 2,-NHC 1-6-alkyl and-N (C 1-6-alkyl) 2; Wherein aryl, cycloalkyl, heteroaryl or Heterocyclylalkyl, separately or as the part of another part, optionally by one, two or three R 7replace; R wherein 7cN, NO 2, halogen, oxo, C 1-6alkyl, aryl, C 3-8cycloalkyl, heteroaryl, Heterocyclylalkyl, OR m, SR m, C (O) R m, C (O) NR nr o, C (O) OR m, OC (O) R m, OC (O) NR nr o, NR nr o, NR nc (O) R m, S (O) R m, S (O) NR nr o, S (O) 2r m, NR ns (O) 2r mor S (O) 2nR nr o, C wherein 1-6-alkyl is optionally selected from following substituting group and replaces by one or more: CN, halogen, hydroxyl, C 1-6-alkoxyl group, Heterocyclylalkyl, cycloalkyl, aryl, heteroaryl ,-NH 2,-NHC 1-6-alkyl and-N (C 1-6-alkyl) 2, wherein aryl, C 3-8cycloalkyl, heteroaryl and Heterocyclylalkyl, separately or as the part of another part, optionally by one, two or three replace independently selected from following substituting group: CN, halogen and C 1-6alkyl.In another embodiment of formula (IV), R 7c 1-6-alkyl, C 1-6haloalkyl, or C (O) R m; R mc 1-6alkyl, C 1-6haloalkyl or C 3-8cycloalkyl.
In an embodiment of formula (IV), R 4be phenyl, wherein phenyl is by Heterocyclylalkyl and optional one or two R 5replace, wherein R 5halogen, C 1-6alkyl, C 1-6haloalkyl or OR g, wherein Heterocyclylalkyl is optionally by one, two or three R 7replace; R wherein 7cN, NO 2, halogen, oxo, C 1-6alkyl, aryl, C 3-8cycloalkyl, heteroaryl, Heterocyclylalkyl, OR m, SR m, C (O) R m, C (O) NR nr o, C (O) OR m, OC (O) R m, OC (O) NR nr o, NR nr o, NR nc (O) R m, S (O) R m, S (O) NR nr o, S (O) 2r m, NR ns (O) 2r mor S (O) 2nR nr o, C wherein 1-6-alkyl is optionally selected from following substituting group and replaces by one or more: CN, halogen, hydroxyl, C 1-6-alkoxyl group, Heterocyclylalkyl, cycloalkyl, aryl, heteroaryl ,-NH 2,-NHC 1-6-alkyl and-N (C 1-6-alkyl) 2, wherein aryl, C 3-8cycloalkyl, heteroaryl and Heterocyclylalkyl, separately or as the part of another part, optionally by one, two or three replace independently selected from following substituting group: CN, halogen and C 1-6alkyl.In another embodiment of formula (IV), R 5heterocyclylalkyl is piperazinyl, Diazesuberane base, piperidyl, pyrrolidyl, morpholinyl, hexahydropyrrolo also [1, 2-a] pyrazinyl, oxo piperazinyl, (1S, 4S)-2, 5-diazabicyclo [2.2.1] heptan-2-base, (1R, 4R)-2, 5-diazabicyclo [2.2.1] heptan-2-base, 6-oxo-1, 4, 5, 6-tetrahydro pyridazine-3-base, octahydro-2H-quinolizinyl, 3, 7-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-3-base, (8aR)-hexahydropyrrolo also [1, 2-a] pyrazine-2 (1H)-Ji, octahydro-2H-pyrido [1, 2-a] pyrazine-2-base, thiazolidine-2-Ji, 4-oxo-1, 3-thiazolidine-2-Ji, (3R)-1-azabicyclo [2.2.2] oct-3-yl or thio-morpholinyl.
In another embodiment of formula (IV), R 4be
Figure 43657DEST_PATH_IMAGE027
Figure 621269DEST_PATH_IMAGE028
Figure DEST_PATH_IMAGE045
。
R wherein 5halogen, C 1-6-alkyl, C 1-6haloalkyl or OR g; P is 0 or 1; R 7cN, NO 2, halogen, C 1-6-alkyl, C 1-6-haloalkyl, OR m, SR m, C (O) R m, C (O) NR nr o, C (O) OR m, NR nr o, NR nc (O) R m, S (O) 2r m, NR ns (O) 2r mor S (O) 2nR mr o; Q is 0 or 1.
In an embodiment of formula (IV), R 3be phenyl, wherein phenyl is selected from following substituting group by one and replaces: C 1-6-alkyl, C 1-6-haloalkyl, halogen and OR d;
R 4be ; R 5halogen, C 1-6alkyl, C 1-6haloalkyl or OR g; P is 0 or 1.
In an embodiment of formula (IV), R 4be
R wherein 5halogen, C 1-6alkyl, C 1-6haloalkyl or OR g; R gbe selected from H, C 1-6alkyl, aryl, C 3-8cycloalkyl, heteroaryl and Heterocyclylalkyl; C wherein 1-6-alkyl is optionally selected from following substituting group and replaces by one or more: CN, halogen, hydroxyl, C 1-6-alkoxyl group, Heterocyclylalkyl ,-NH 2,-NHC 1-6-alkyl and-N (C 1-6-alkyl) 2, wherein aryl, C 3-8cycloalkyl, heteroaryl or Heterocyclylalkyl, separately or as the part of another part, be optionally selected from following substituting group and replace by one or more: halogen, C 1-6-alkyl, C 1-6-haloalkyl, C 1-6-hydroxyalkyl, hydroxyl, oxo, C 1-6-alkoxyl group, C 1-6-halogenated alkoxy, C (O) C 1-6-alkyl, S (O) 2c 1-6-alkyl ,-NH 2,-NH (C 1-6-alkyl) ,-N (C 1-6-alkyl) 2with-N (C 1-6-alkyl) (C 3-8-cycloalkyl); R hand R iwhen occurring at every turn independently selected from H, C 1-6alkyl, aryl, C 3-8cycloalkyl, heteroaryl and Heterocyclylalkyl; C wherein 1-6-alkyl is optionally selected from following substituting group and replaces by one or more: CN, halogen, hydroxyl, C 1-6-alkoxyl group, Heterocyclylalkyl ,-NH 2,-NHC 1-6-alkyl and-N (C 1-6-alkyl) 2, wherein aryl, C 3-8cycloalkyl, heteroaryl or Heterocyclylalkyl, separately or as the part of another part, be optionally selected from following substituting group and replace by one or more: halogen, C 1-6-alkyl, C 1-6-haloalkyl, C 1-6-hydroxyalkyl, hydroxyl, oxo, C 1-6-alkoxyl group, C 1-6-halogenated alkoxy, C (O) C 1-6-alkyl, S (O) 2c 1-6-alkyl ,-NH 2,-NH (C 1-6-alkyl), N (C 1-6-alkyl) 2with-N (C 1-6-alkyl) (C 3-8-cycloalkyl); P is 0,1 or 2.
In an embodiment of formula (IV), R 4be 5-16 unit monocycle, dicyclo or tricyclic heterocyclic base, wherein heterocyclic radical is optionally by one or more R 6replace R 6cN, NO 2, halogen, C 3-8cycloalkyl, OR j, SR j, C (O) R j, C (O) NR kr l, C (O) OR j, NR kr l, NR kc (O) R j, S (O) 2r j, NR ks (O) 2r jor S (O) 2nR kr l, C wherein 1-6-alkyl is optionally selected from following substituting group and replaces by one or more: CN, halogen, hydroxyl, C 1-6-alkoxyl group, Heterocyclylalkyl, cycloalkyl, heteroaryl, aryl ,-NH 2,-NHC 1-6-alkyl and-N (C 1-6-alkyl) 2; Wherein Heterocyclylalkyl, cycloalkyl, heteroaryl, aryl, separately or as the part of another part, optionally by one, two or three replace independently selected from following substituting group: CN, halogen, heteroaryl, benzyl and C 1-6alkyl.
In an embodiment of formula (IV), R 4it is 4-8 unit monocyclic heterocycles base.In another embodiment, R 44-8 unit's Heterocyclylalkyl or heterocycloalkenyl.In another embodiment, R 4it is 5-7 unit heteroaryl.In another embodiment of formula (IV), R 4pyrrolidyl, tetrahydrofuran base, tetrahydro-thienyl, imidazolidyl, pyrazolidyl, piperidyl, Diazesuberane base, THP trtrahydropyranyl, piperazinyl, alkyl dioxin, thiazolidine-2-Ji, morpholinyl, 2-oxo-pyrrolidine base, 4-oxo-1,3-thiazoles alkane-2-base, thio-morpholinyl, 2,5-dioxo pyrrolidyl, 2-oxo-piperidine base, 4-oxo-piperidine base or 2,6-dioxopiperidine base.In another embodiment of formula (I), R 4pyridyl (pyridyl), pyrazinyl (pyrazyl), pyridyl (pyridinyl), pyrimidyl, pyridazinyl, 1,3,5-, 1,2,4-or 1,2,3-triazinyl, imidazolyl, furyl, thienyl, pyrazolyl ， oxazolyl ， isoxazolyl, thiazolyl, 1,2,3-, 1,2,4-, 1,2,5-or 1,3,4-oxadiazolyl, or isothiazolyl.In one embodiment, R 4unsubstituted.In another embodiment, R 4by one, two or three R 6replace R 6halogen, C 1-6-alkyl, C 1-6-haloalkyl, OR j, C (O) R j, NR kr lor S (O) 2r j.
In an embodiment of formula (IV), R 4it is 7-11 unit bicyclic heterocyclic radical.In another embodiment, R 47-11 unit's bicyclic heterocycle alkyl or bicyclic heterocycle thiazolinyl.In another embodiment, R 4it is 7-11 unit bicyclic heteroaryl.In another embodiment, R 42, 3-dihydro-2-oxo--1H-indyl, hexahydropyrrolo also [1, 2-a] pyrazinyl, (1R, 4R)-2, 5-diazabicyclo [2.2.1] heptan-2-base, benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolyl, quinolyl-N-oxide compound, tetrahydro isoquinolyl, isoquinolyl, benzimidazolyl-, benzopyranyl, indolizinyl, benzofuryl, chromone base, tonka bean camphor base, scold Lin Ji, quinoxalinyl, indazolyl, pyrrolopyridinyl, furo pyridyl, dihydro-iso indolyl, dihydroquinazoline base, 3, 4-dihydro-4-oxo-quinazolyl, 6-oxo-1, 4, 5, 6-tetrahydro pyridazine-3-base, octahydro-2H-quinolizinyl, 3, 7-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-3-base, (8aR)-hexahydropyrrolo also [1, 2-a] pyrazine-2 (1H)-Ji, benzisothiazole base, benzoisoxazole base, benzo two azine groups, benzofuraxan base, benzo thiapyran base, octahydro-2H-pyrido [1, 2-a] pyrazine-2-base, benzotriazole base, phenylpyrazole base, 1, 3-benzodioxole base, (3R)-1-azabicyclo [2.2.2] oct-3-yl, dihydro benzo furyl, dihydrobenzo thienyl, thiochroman base, thiochroman base sulfone, dihydrobenzopyrans base, Er hydrogen benzoxazinyl, 3-oxo-3, 4-dihydro-1, 4-benzoxazinyl, indolinyl, indazolyl, 4-oxo-1, 4-dihydro cinnolines-6-base, isochroman base, isoindolinyl, naphthyridinyl, phthalazinyl, piperonyl, purine radicals, pyridopyridine base, pyrrolotriazine base, quinazolyl, 1, 2, 3-diazosulfide-5-base, 1, 3-benzothiazol-6-yl, tetrahydric quinoline group, thienofuran base, thienopyridine base, [1, 2-a] pyridine-2-base, 2, 3-glyoxalidine also [2, 1-b] [1, 3] thiazole-6-base, imidazo [2, 1-b] [1, 3] thiazole-6-base, 3-oxo-2, 3-dihydro-1H-indazole-7-base, 5, 6, 7, 8-tetrahydrochysene-1, 6-naphthyridines-3-base, 2, 7-diaza spiro [3.5] ninth of the ten Heavenly Stems-7-base, 2, 6-diaza spiro [3.3] heptan-2-base, 2, 6-diaza spiro [3.4] is pungent-2-base, 2, 7-diaza spiro [3.5] ninth of the ten Heavenly Stems-2-base, 3, 0-diaza spiro [5.5] 10 one-3-bases, (3aR, 6aR)-hexahydropyrrolo also [3, 4-b] pyrroles-1 (2H)-Ji, 2, 3, 4, 5-tetrahydrochysene-1H-2-benzo-aza
Figure 534495DEST_PATH_IMAGE002
base, 2,3,4,5-tetrahydrochysene-1H-3-benzo-aza
Figure 650219DEST_PATH_IMAGE002
base, 1,2,3,4-tetrahydroisoquinoline-7-base, 1,2,3,4-tetrahydric quinoline group, 4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-base, 2,3-dihydro-1H-indoles-5-base, indolinyl, 2,3-dihydro-1H-indazolyl, isoindolinyl, 1,2,3,4-tetrahydroisoquinoline-6-base or thienothiophene base.In an embodiment of formula (I), R 4unsubstituted.In another embodiment of formula (II), R 4by one, two or three R 6replace R 6cN, NO 2, halogen, C 3-8cycloalkyl, OR j, SR j, C (O) R j, C (O) NR kr l, C (O) OR j, NR kr l, NR kc (O) R j, S (O) 2r j, NR ks (O) 2r jor S (O) 2nR kr l, C wherein 1-6-alkyl is optionally selected from following substituting group and replaces by one or more: CN, halogen, hydroxyl, C 1-6-alkoxyl group, Heterocyclylalkyl, cycloalkyl, heteroaryl, aryl ,-NH 2,-NHC 1-6-alkyl and-N (C 1-6-alkyl) 2; Wherein Heterocyclylalkyl, cycloalkyl, heteroaryl, aryl, separately or as the part of another part, optionally by one, two or three replace independently selected from following substituting group: CN, halogen, heteroaryl, benzyl and C 1-6alkyl.
In an embodiment of formula (IV), R 4be
Figure 285173DEST_PATH_IMAGE014
Figure 577614DEST_PATH_IMAGE015
Figure 191315DEST_PATH_IMAGE017
Figure 655925DEST_PATH_IMAGE018
or
Figure 96451DEST_PATH_IMAGE020
。
In an embodiment of formula (IV), R 4it is 10-15 unit tricyclic heterocyclic base.In another embodiment, R 410-15 unit's tricyclic heterocyclic alkyl or tricyclic heterocyclic thiazolinyl.In another embodiment, R 4it is 10-15 unit tricyclic heteroaryl.In an embodiment of formula (IV), R 4be 5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base or 2' also, 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-base.In an embodiment of formula (IV), R 4unsubstituted.In another embodiment of formula (IV), R 4by one, two or three R 6replace R 6halogen, C 1-6-alkyl, C 1-6-haloalkyl, OR j, C (O) R j, NR kr lor S (O) 2r j.
In an embodiment of formula (IV), R 4be
Figure DEST_PATH_IMAGE047
。
In one embodiment, the present invention partly relates to the compounds category with formula (IVa) structure
Figure 707561DEST_PATH_IMAGE048
R wherein 4described in formula (IV), R pand R qhalogen or hydrogen independently.
Compound as the included specific embodiments of a part of the present invention including, but not limited to following formula (I), for example:
6-(2-chloro-phenyl-)-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-anilino-6-(2-chloro-phenyl-) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(pyridin-4-yl is amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-[(2'-methyl-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(5,6,7,8-naphthane-2-base is amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[3-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-[(4-cyclohexyl phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(piperidin-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(pyrrolidin-1-yl methyl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(morpholine-4-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[3-(pyrrolidin-1-yl methyl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-[(1-ethanoyl-2,3-dihydro-1H-indoles-6-yl) amino]-6-(2-chloro-phenyl-) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-{[4-(4-ethanoyl piperazine-1-yl) phenyl] amino }-6-(2-chloro-phenyl-) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-aminomethyl phenyl)-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-{[4-(4-methylpiperazine-1-yl) phenyl] amino }-6-[2-(trifluoromethyl) phenyl] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-p-methoxy-phenyl)-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[2-methoxyl group-4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-[(1-methyl isophthalic acid, 2,3,4-tetrahydroquinoline-7-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
7-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino }-3,4-dihydro-isoquinoline-2 (1H)-formic acid tertiary butyl ester;
6-(2-chloro-phenyl-)-2-(1,2,3,4-tetrahydroisoquinoline-7-base is amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[3-methyl-4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-allyl group-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-cyclohexyl-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-9-methyl-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } Kui Linpyrimido quinoline [5,4-e] [1,2,4] triazolos [4,3-a] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-9-methyl-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } Kui Linpyrimido quinoline [5,4-e] [1,2,4] triazolos [4,3-a] pyrimidine-5 (6H)-one;
4-(2-chloro-phenyl-)-8-{[4-(4-methylpiperazine-1-yl) phenyl] amino } Kui Linpyrimido quinoline [5,4-e] tetrazolo [1,5-a] pyrimidine-5 (4H)-one;
6-(2-chloro-phenyl-)-2-(4-[4-(third-2-yl) piperazine-1-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(4-[4-(cyclohexyl methyl) piperazine-1-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
3-{[4-(4-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } phenyl) piperazine-1-yl] methyl } benzonitrile;
The chloro-4-of 2-{[3-(4-methylpiperazine-1-yl) phenyl] amino }-6-(2-chloro-phenyl-) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(the fluoro-4-[4-of 3-(third-2-yl) piperazine-1-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-[(2-methyl isophthalic acid, 2,3,4-tetrahydroisoquinoline-7-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(4-[2-(dimethylamino) oxyethyl group] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(4-[2-(morpholine-4-yl) oxyethyl group] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[3-methyl-4-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(1-methyl piperidine-4-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-{[4-(4-methylpiperazine-1-yl) phenyl] amino }-6-phenylimidazole [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one also;
6-(the chloro-4-aminomethyl phenyl of 2-)-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
4-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino }-N-phenylcyclohexane methane amide;
6-(2-chloro-phenyl-)-2-(4-[(4-methylpiperazine-1-yl) and carbonyl] phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(1H-pyrazoles-4-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(4-[2-(diethylamino) oxyethyl group] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(pyridin-3-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
4-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino }-N-(trans-4-hydroxy-cyclohexyl) benzamide;
4-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino }-N-ethyl benzamide;
6-(2-chloro-phenyl-)-2-(4-[(4-hydroxy piperidine-1-yl) and carbonyl] phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
4-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino }-N-(pyridin-4-yl) benzamide;
6-(2-chloro-phenyl-)-2-(4-[3-(diethylamino) propoxy-] and-3-fluorophenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(the fluoro-4-[2-of 3-(4-methylpiperazine-1-yl) oxyethyl group] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[2-(2-methoxy ethyl)-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-[(2,4,4-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-7-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(3-hydroxy-2-methyl phenyl)-2-(phenyl amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-[(4-aminophenyl) amino]-6-(2-chloro-phenyl-) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
N-(4-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } phenyl) ethanamide;
N-(4-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } phenyl) ring penta methane amide;
N-(4-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } phenyl)-4-hydroxyl cyclohexane carboxamide;
N-(4-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } phenyl)-1-methyl piperidine-4-methane amide;
N-(4-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } phenyl) pyridine-4-methane amide;
6-(2,6-3,5-dimethylphenyl)-2-[(2'-methyl-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-(4-[4-(3-chlorobenzyl) piperazine-1-yl] and phenyl } amino)-6-(2-chloro-phenyl-) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(4-[4-(2-methoxy ethyl) piperazine-1-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[3-methoxyl group-4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(3-methoxyl group-4-[4-(third-2-yl) piperazine-1-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(3-methoxyl group-4-[2-(4-methylpiperazine-1-yl) oxyethyl group] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(3-hydroxy phenyl)-2-(phenyl amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-[(4-aminomethyl phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(piperidin-2-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(pyrrolidin-2-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(pyrrolidin-3-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-[(2'-methyl-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[3-methyl-4-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(piperazine-1-yl)-3-(trifluoromethyl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(4-[(2S) and-pyrrolidin-2-yl methoxyl group] phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(2-methyl-4-[3-(4-methylpiperazine-1-yl) propoxy-] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(morpholine-4-ylmethyl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(1H-imidazoles-1-ylmethyl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(1H-imidazoles-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[6-(piperazine-1-yl) pyridin-3-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(3-[3-(4-methylpiperazine-1-yl) propoxy-] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(3-[3-(piperidin-1-yl) propoxy-] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-(phenyl amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(3-methoxyl group-4-[2-(third-2-base is amino) oxyethyl group] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(the chloro-4-[2-of 3-(third-2-base is amino) oxyethyl group] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(methylol) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(1H-pyrazol-1-yl methyl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(1H-pyrazol-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-base amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-[(2'-ethanoyl-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl) amino]-6-(2-chloro-phenyl-) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-[(1-methyl isophthalic acid, 2,3,4-tetrahydroquinoline-6-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(1-[2-(dimethylamino) ethyl] and-2,3-dihydro-1H-indoles-5-yl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[2-(dimethylamino)-2,3-dihydro-1H-indenes-5-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-{[3-methyl-4-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-[(2,4,4-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-7-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-difluorophenyl)-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[2-(2-hydroxyethyl)-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[3-(methylol)-4-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(hexahydropyrrolo is [1,2-a] pyrazine-2 (1H)-yl also) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-[(4-hydroxy-3-methyl phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(4-[3-(diethylamino) propoxy-] and-3-aminomethyl phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[3-methyl-4-(piperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(Isosorbide-5-Nitrae-Diazesuberane-1-yl)-3-aminomethyl phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(2,3,4,5-tetrahydrochysene-1H-2-benzo-aza
Figure 107187DEST_PATH_IMAGE002
-7-base is amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-[(3-methyl-2,3,4,5-tetrahydrochysene-1H-3-benzo-aza
Figure 374220DEST_PATH_IMAGE002
-7-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-[(1,1,2-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-7-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-(2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-base amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[3-methyl-4-(piperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-(1,2,3,4-tetrahydroisoquinoline-7-base is amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[3-ethyl-4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[2-(cyclohexyl methyl)-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[2-(dimethylamino)-2,3-dihydro-1H-indenes-5-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-(4-[4-(third-2-yl) piperazine-1-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[4-(hexahydropyrrolo is [1,2-a] pyrazine-2 (1H)-yl also) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[2-(2-ethyl-butyl)-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-(4-[2-(4-methylpiperazine-1-yl) ethyl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-(1-[2-(dimethylamino) ethyl] and-2,3-dihydro-1H-indoles-5-yl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[3-ethyl-4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[3-(methylol)-4-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-(1,2,3,4-tetrahydroisoquinoline-6-base is amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-4-fluorophenyl of 2,6-bis-)-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-4-fluorophenyl of 2,6-bis-)-2-{[3-methyl-4-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-4-fluorophenyl of 2,6-bis-)-2-[(2'-methyl-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-4-fluorophenyl of 2,6-bis-)-2-{[2-(dimethylamino)-2,3-dihydro-1H-indenes-5-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-(4-[(4-methylpiperazine-1-yl) and methyl] phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-(4-[(3R, 5S) and-3,5-lupetazin-1-yl]-3-fluorophenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[3, the fluoro-4-of 5-bis-(piperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[2-(cyclopropyl methyl)-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4,4-dimethyl-2-(pyridin-3-yl methyl)-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4,4-dimethyl-2-(thiene-3-yl-methyl)-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-[(1,1,2-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-6-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[4-(pyrrolidin-2-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[4-(piperidin-2-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
The chloro-4-of 2-{[3-(4-methylpiperazine-1-yl) phenyl] amino }-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-(3-methoxyl group-4-[4-(third-2-yl) piperazine-1-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(4-hydroxy piperidine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-{[2-(dimethylamino)-2,3-dihydro-1H-indenes-5-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-[(2'-methyl-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-{[4-(Isosorbide-5-Nitrae-Diazesuberane-1-yl)-3-aminomethyl phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-[(2'-methyl-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl) amino]-6-(third-2-yl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[4-(3-oxo piperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4,4-dimethyl-2-(third-2-yl)-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4,4-dimethyl-2-(4,4,4-trifluoro butyl)-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-[(1,1,2-trimethylammonium-2,3-dihydro-1H-isoindole-5-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-[(1,1,2,3,3-pentamethyl--2,3-dihydro-1H-isoindole-5-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[3-methoxyl group-4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-(4-[3-(diethylamino) propoxy-] and-3-fluorophenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-[(1,1,2-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-6-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-(4-[(1S, 4S) and-2,5-diazabicyclo [2.2.1] heptan-2-yl] phenyl } amino)-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-[(2,4,4-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-7-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[4-(4,4-difluoro piperidin-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[4-(3,3-difluoro piperidin-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-(the fluoro-4-[4-of 3-(third-2-yl) piperazine-1-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[4-(piperazine-1-yl)-3-(trifluoromethyl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(4-methylpiperazine-1-yl)-3-(third-2-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-{[4-(4-ethanoyl piperazine-1-yl) phenyl] amino }-6-(the chloro-6-fluorophenyl of 2-) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-[(4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-4-fluorophenyl of 2,6-bis-)-2-(2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-base amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-[(2-ethyl-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4,4-dimethyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(2-[4-(1H-imidazoles-1-yl) benzyl] and-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-(2-[(1-benzyl piepridine-4-yl) and methyl]-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl } amino)-6-(2-chloro-phenyl-) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-[(2'-ethanoyl-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl) amino]-6-(the chloro-4-fluorophenyl of 2,6-bis-) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[4-(4-hydroxy piperidine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-[(4-cyclohexyl phenyl) amino]-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[4-(pyrrolidin-3-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[4-(morpholine-4-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[4,4-dimethyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-{[2'-(cyclopropyl carbonyl)-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl] amino-6-(the chloro-4-fluorophenyl of 2,6-bis-) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-4-fluorophenyl of 2,6-bis-)-2-{[2'-(methylsulfonyl)-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl] amino imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-4-fluorophenyl of 2,6-bis-)-2-{[6-(piperazine-1-yl) pyridin-3-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[4-(2-oxo piperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-(4-[(1R, 4R) and-2,5-diazabicyclo [2.2.1] heptan-2-yl] phenyl } amino)-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[4-(4-methylpiperazine-1-yl)-3-(third-2-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-[(1,1,2,3,3-pentamethyl--2,3-dihydro-1H-isoindole-5-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-[(1,1,2-trimethylammonium-2,3-dihydro-1H-isoindole-5-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
(3aS, 10aS)-8-{[6-(2,6-dichlorophenyl)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino }-2,3,3a, 5,10,10a-hexahydropyrrolo is [3,4-c] [1] benzo-aza also
Figure 901017DEST_PATH_IMAGE002
-4 (1H)-one;
6-(2,6-dichlorophenyl)-2-{[4-(6-oxo-Isosorbide-5-Nitrae, 5,6-tetrahydro pyridazine-3-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-(1,2,3-diazosulfide-5-base is amino)-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-(1,3-benzothiazol-6-yl is amino)-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-(4-[bis-(2-methoxy ethyl) amino] and phenyl } amino)-6-(2-chloro-phenyl-) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-[(3-cyclopropyl-2,3,4,5-tetrahydrochysene-1H-3-benzo-aza -7-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[3-(2,2-, bis-fluoro ethyls)-2,3,4,5-tetrahydrochysene-1H-3-benzo-aza
Figure 563259DEST_PATH_IMAGE002
-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-4,6-difluorophenyl)-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-4,6-difluorophenyl)-2-[(2,4,4-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-7-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-4,6-difluorophenyl)-2-{[2-(dimethylamino)-2,3-dihydro-1H-indenes-5-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-[(4-{[3-(morpholine-4-yl) propyl group] amino } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(4-[4-(pyrrolidin-1-yl) piperidin-1-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(4-[4-(dimethylamino) piperidin-1-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-[(4-{[2-(1-methylpyrrolidin-2-yl) ethyl] amino } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
4-{[6-(2,6-dichlorophenyl)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } phenylformic acid 4-(dimethylamino) cyclohexyl ester;
6-(2,6-dichlorophenyl)-2-(1H-indazole-5-base is amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-(4-[(3S) and-3-(third-2-yl) piperazine-1-yl] phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-[(4-{1-[1-(dimethylamino)-3-methyl butyl] cyclobutyl } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-(4-[4-methyl-2-(methylamino)-1,3-thiazoles-5-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[6-(piperazine-1-yl) pyridin-3-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-(1H-indazole-6-base is amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
4-{[6-(2,6-dichlorophenyl)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } phenylformic acid (1R)-octahydro-2H-quinolizine-1-base ester;
4-{[6-(2,6-dichlorophenyl)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } phenylformic acid 2-[cyclopropyl (methyl) amino] ethyl ester;
6-(2,6-dichlorophenyl)-2-[(4-{[(1R, 5S)-7-ethyl-3,7-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-3-yl] carbonyl } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[3, the fluoro-4-of 5-bis-(piperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-({ 4-[(8aR)-hexahydropyrrolo is [1,2-a] pyrazine-2 (1H)-yl also] phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-(2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-base amino)-6-(4-hydroxy phenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[2'-(methylsulfonyl)-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl] amino imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-[(2'-ethanoyl-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl) amino]-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(octahydro-2H-pyrido [1,2-a] pyrazine-2-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-[(1,1,2-trimethylammonium-2,3-dihydro-1H-isoindole-5-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-[(1,1,2,3,3-pentamethyl--2,3-dihydro-1H-isoindole-5-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(4-[4-(trimethylene oxide-3-yl) piperazine-1-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-4-fluorophenyl of 2,6-bis-)-2-[(2,4,4-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-7-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-[(4-oxo-Isosorbide-5-Nitrae-dihydro cinnolines-6-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-{[4-(4-ethanoyl piperazine-1-yl) phenyl] amino }-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-(4-[4-(dimethylamino) piperidin-1-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
4-{[6-(2,6-dichlorophenyl)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } methyl benzoate;
6-(2-chloro-phenyl-)-2-{[3, the chloro-4-of 5-bis-(piperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(imidazo [1,2-a] pyridine-2-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(4-[4-oxo-3-(third-2-yl)-1,3-thiazoles alkane-2-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(2,3-glyoxalidine is [2,1-b] [1,3] thiazole-6-yl also) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(5-methyl-4-oxo-1,3-thiazoles alkane-2-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(imidazo [2,1-b] [1,3] thiazole-6-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(3-oxo-2,3-dihydro-1H-indazole-7-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-{[2'-(2,2-, bis-fluoro ethyls)-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl] amino imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-{[2'-(2-fluoro ethyl)-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl] amino imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-{[2'-(2-fluoro ethyl)-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl] amino imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-{[2-(diethylamino)-2,3-dihydro-1H-indenes-5-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-{[2-(diethylamino)-2,3-dihydro-1H-indenes-5-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-{[2-(cyclopropylamino)-2,3-dihydro-1H-indenes-5-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-{[2-(cyclopropylamino)-2,3-dihydro-1H-indenes-5-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-(2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-base amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-{[4-(Isosorbide-5-Nitrae '-Lian piperidines-1'-yl) phenyl] amino-6-(2-chloro-phenyl-) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(4-[(3R) and-3-(dimethylamino) pyrrolidin-1-yl] phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(4-[3-(trifluoromethyl) piperidin-1-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
3-[4-(4-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } phenyl) piperazine-1-yl] propionitrile;
3-[(4-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } phenyl) (cyclopropyl) amino] propionitrile;
6-(2-chloro-phenyl-)-2-[(4-{[2-(dimethylamino) ethyl] amino } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
1-(4-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } phenyl) piperidines-4-methane amide;
6-(2-chloro-phenyl-)-2-(4-[4-(morpholine-4-yl) piperidin-1-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-[(4-{[4-(dimethylamino) piperidin-1-yl] carbonyl } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
4-{[6-(2,6-dichlorophenyl)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino }-N-[4-(dimethylamino) cyclohexyl] benzamide;
4-{[6-(2,6-dichlorophenyl)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino }-N-(1-methyl piperidine-4-yl) benzamide;
6-(2,6-dichlorophenyl)-2-(4-[4-(pyrrolidin-1-yl) piperidin-1-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-[(2'-ethanoyl-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl) amino]-6-(the chloro-6-fluorophenyl of 2-) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-{[2'-(cyclopropyl carbonyl)-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl] amino imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-{[2'-(methylsulfonyl)-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl] amino imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-({ 4-[(8aR)-hexahydropyrrolo is [1,2-a] pyrazine-2 (1H)-yl also] phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-(4-[(3R) and-1-azabicyclo [2.2.2] oct-3-yl amino] phenyl } amino)-6-(2-chloro-phenyl-) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-[(4-{[2-(pyrrolidin-1-yl) ethyl] amino } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(4-[4-(pyridine-2-yl) piperazine-1-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-[(4-{[2-(morpholine-4-yl) ethyl] amino } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(4-[(2S) and-2-(pyrrolidin-1-yl methyl) pyrrolidin-1-yl] phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-[(4-{4-[3-(dimethylamino) propyl group] piperazine-1-yl } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(4-[(2R) and-2-(methoxymethyl) pyrrolidin-1-yl] phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
1-(4-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } phenyl)-N, N-diethyl piperidines-3-methane amide;
6-(2-chloro-phenyl-)-2-[(4-{[3-(2-oxo-pyrrolidine-1-yl) propyl group] amino } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(4-[4-(4-fluorophenyl) piperazine-1-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-(4-[4-(dimethylamino) piperidin-1-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-(2-[(3S) and-3-fluoropyrrolidine-1-yl]-2,3-dihydro-1H-indenes-5-yl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-(2-[(3S) and-3-fluoropyrrolidine-1-yl]-2,3-dihydro-1H-indenes-5-yl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-(2-[(2-fluoro ethyl) and amino]-2,3-dihydro-1H-indenes-5-yl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-(2-[(2-fluoro ethyl) and amino]-2,3-dihydro-1H-indenes-5-yl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-{[2-(propyl group is amino)-2,3-dihydro-1H-indenes-5-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-{[2-(propyl group is amino)-2,3-dihydro-1H-indenes-5-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-{[2-(pyrrolidin-1-yl)-2,3-dihydro-1H-indenes-5-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-[(4-{4-[2-(dimethylamino) ethyl] piperazine-1-yl } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-[(4-{[3-(dimethylamino) propyl group] (methyl) amino } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-[(4-{[2-(dimethylamino) ethyl] (ethyl) amino } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-[(4-{[2-(dimethylamino) ethyl] (methyl) amino } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(4-[(2S) and-2-(methoxymethyl) pyrrolidin-1-yl] phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-{[2'-(2-methylpropionyl)-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl] amino imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-{[2'-(2,2-dimethyl propylene acyl group)-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl] amino imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-{[2'-(cyclopentylcarbonyl)-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl] amino imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-[(4-{[2-(1H-imidazol-4 yl) ethyl] amino } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-[(4-{[3-(1H-imidazoles-1-yl) propyl group] amino } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(thiomorpholine-4-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-[(4-{ third-2-base [2-(third-2-base is amino) ethyl] amino } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
1-(4-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } phenyl) piperidines-3-methane amide;
6-(2,6-dichlorophenyl)-2-[(4-{[2-(1-methylpyrrolidin-2-yl) ethyl] amino } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[2'-(2-methylpropionyl)-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl] amino imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-{[2'-(cyclopropyl carbonyl)-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl] amino-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[2'-(2,2-dimethyl propylene acyl group)-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl] amino imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-(5,6,7,8-tetrahydrochysene-1,6-naphthyridines-3-base is amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-3-hydroxyl phenyl)-2-(2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-base amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-(2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-base amino)-6-(4-hydroxy-2-methyl phenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-{[2-(2,2-, bis-fluoro ethyls)-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-{[2-(2-fluoro ethyl)-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-{[4-(Isosorbide-5-Nitrae '-Lian piperidines-1'-yl) phenyl] amino-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-(4-[(3R) and-3-(dimethylamino) pyrrolidin-1-yl] phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-[(4-{[2-(dimethylamino) ethyl] amino } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-{[2'-(cyclopropyl alkylsulfonyl)-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl] amino-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[2'-(third-2-base alkylsulfonyl)-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl] amino imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[4-(1-methyl piperidine-4-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-{[4-(2,7-diaza spiro [3.5] ninth of the ten Heavenly Stems-7-yl) phenyl] amino }-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(4-[2-(trifluoromethyl) pyrrolidin-1-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(piperidin-4-yl oxygen base) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(piperidin-4-ylmethyl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(hexahydropyrrolo is [3,4-c] pyrroles-2 (1H)-yl also) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
1-(4-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } phenyl)-N-methyl Toluidrin;
4-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino }-N, N-diethyl benzene sulfonamide;
2-{[2-(cyclopropylamino)-2,3-dihydro-1H-indenes-5-yl] amino }-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-(2-[(2-fluoro ethyl) and amino]-2,3-dihydro-1H-indenes-5-yl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[2-(propyl group is amino)-2,3-dihydro-1H-indenes-5-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-{[4-(2-ethanoyl-2,7-diaza spiro [3.5] ninth of the ten Heavenly Stems-7-yl) phenyl] amino }-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-(4-[2-(methylsulfonyl)-2,7-diaza spiro [3.5] ninth of the ten Heavenly Stems-7-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
7'-{[6-(the chloro-6-fluorophenyl of 2-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino }-N-methyl isophthalic acid ' H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-2'(3'H)-methane amide;
7'-{[6-(the chloro-6-fluorophenyl of 2-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino }-N-(third-2-yl)-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-2'(3'H)-methane amide;
6-(2,6-dichlorophenyl)-2-{[2-(2-fluoro ethyl)-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-(4-[6-(methylsulfonyl)-2,6-diaza spiro [3.3] heptan-2-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[2-(pyrrolidin-1-yl)-2,3-dihydro-1H-indenes-5-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-(2-[(3S) and-3-fluoropyrrolidine-1-yl]-2,3-dihydro-1H-indenes-5-yl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-[(4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[4-(piperidin-4-yl is amino) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-{[4-(1-methyl piperidine-4-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-[(2-ethanoyl-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl) amino]-6-(the chloro-6-fluorophenyl of 2-) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-{[2-(cyclopropyl carbonyl)-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-{[4,4-dimethyl-2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-{[4-(2,6-diaza spiro [3.4] pungent-2-yl) phenyl] amino }-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-{[4-(2,7-diaza spiro [3.5] ninth of the ten Heavenly Stems-2-yl) phenyl] amino }-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-(4-[(3S) and-3-(dimethylamino) pyrrolidin-1-yl] phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-{[2-(hydroxyacetyl)-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
7-{[6-(the chloro-6-fluorophenyl of 2-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino }-4,4-dimethyl-3,4-dihydro-isoquinoline-2 (1H)-sulphonamide;
2-[(2-ethanoyl-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl) amino]-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[4,4-dimethyl-2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[2-(ethylsulfonyl)-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-(4-[(1-ethanoyl piperidin-4-yl) and amino] phenyl } amino)-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-[(4-{[1-(methylsulfonyl) piperidin-4-yl] amino } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[4-(9-methyl-3,9-diaza spiro [5.5] 10 one-3-yls) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-(4-[6-(methylsulfonyl)-2, and 6-diaza spiro [3.4] is pungent-2-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-({ 4-[(8aS)-hexahydropyrrolo is [1,2-a] pyrazine-2 (1H)-yl also] phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-({ 4-[(3aR, 6aR)-5-methyl hexahydropyrrolo is [3,4-b] pyrroles-1 (2H)-yl also] phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-[(4-{[2-(dimethylamino) ethyl] (ethyl) amino } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-[(4-{ third-2-base [2-(third-2-base is amino) ethyl] amino } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-[(2-ethanoyl-1,2,3,4-tetrahydroisoquinoline-7-yl) amino]-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-[(2-ethanoyl-1,2,3,4-tetrahydroisoquinoline-6-yl) amino]-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-thioketones;
6-(2-chloro-phenyl-)-5-imino--N-[4-(4-methylpiperazine-1-yl) phenyl]-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-amine also;
6-(2-chloro-phenyl-)-2-[(2,4,4-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-7-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-thioketones;
6-(2-chloro-phenyl-)-5-imino--N-(2,4,4-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-7-yl)-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-amine also;
6-(3-fluorophenyl)-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(3-chloro-phenyl-)-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,4-Dimethoxyphenyl)-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[5-(4-ethyl piperazidine-1-yl) pyridine-2-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
The chloro-4-of 6-[2-(trifluoromethyl) phenyl]-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-{[4-(4-methylpiperazine-1-yl) phenyl] amino }-6-[2-(trifluoromethoxy) phenyl] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
4-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } phenylformic acid;
2-[(4-bromophenyl) amino]-6-(2-chloro-phenyl-) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(3-methoxyl group-2-aminomethyl phenyl)-2-(phenyl amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-{[4-(Isosorbide-5-Nitrae-Diazesuberane-1-yl)-3-aminomethyl phenyl] amino }-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-{[4-(4-methylpiperazine-1-yl) phenyl] amino }-6-(third-2-yl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[3, the fluoro-4-of 5-bis-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(trifluoromethyl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(1,3-thiazoles-4-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(1,3-thiazoles-2-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(1,8-naphthyridines-2-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(4-[(2S) and-2-(trifluoromethyl) pyrrolidin-1-yl] phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
The chloro-4-of 2-{[3-(4-methylpiperazine-1-yl)-5-(trifluoromethyl) phenyl] amino }-6-(2-chloro-phenyl-) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
The chloro-4-of 6-(2-chloro-phenyl-)-2-{[3-(piperazine-1-yl)-5-(trifluoromethyl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-[(2'-methyl-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-thioketones;
2-{[7-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino }-4,4-dimethyl-3,4-dihydro-isoquinoline-2 (1H)-yl] methyl } benzonitrile;
6-(2-chloro-phenyl-)-2-{[4,4-dimethyl-2-(4-propoxy-benzyl)-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(the fluoro-5-of 2-[3-(trifluoromethyl) benzyl] and-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-[(4-{2-[(2R)-2-methylpyrrolidin-1-yl] ethyl } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(4-[2-(morpholine-4-yl)-1,3-thiazoles-4-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one; With
6-(2-chloro-phenyl-)-2-(4-[2-(6-toluquinoline-2-yl) ethyl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one.
Compound of the present invention can contain the carbon atom of the Asymmetrical substitute of R or S configuration, and wherein term " R " and " S " define as Pure Appl. Chem. (1976) 45,13-10.The compound with the carbon atom (R and the S configuration with equivalent) of Asymmetrical substitute is racemization forms at those atom places.It is excessive that the atom of a configuration excessive (with respect to another configuration) is called as configuration, preferred excessive about 85%-90%, and more preferably excessive about 95%-99%, is more preferably excessive about more than 99%.Correspondingly, the present invention includes the racemic mixture and relative and absolute diastereomer of its compound.
Compound of the present invention can also contain carbon-to-carbon double bond or the two keys of carbon-nitrogen of E or Z configuration, according to definite method of Cahn-Ingold-Prelog priority rule, wherein term " E " represents that high-order substituting group is at two key offsides of carbon-to-carbon or carbon-nitrogen, and term " Z " represents that high-order substituting group is at the homonymy of carbon-to-carbon or the two keys of carbon-nitrogen.Compound of the present invention can also exist with the mixture form of " E " and " Z " isomer.
Other geometrical isomer may reside in the compounds of this invention.For example, the present invention includes by cycloalkyl or heterocyclic group various geometrical isomers and its mixture that around substituent configuration state produces.Cycloalkyl or heterocycle substituting group is around designated as cis or transconfiguration.
Compound of the present invention can also exist with tautomer or its equilibrium mixture form (wherein the proton of compound moves to another atom from an atom).The example of tautomer is including, but not limited to keto-enol, phenol-one base, oxime-nitroso-group, nitro-isonitro (nitro-aci), imines-enamine etc.Although can only describe a tautomeric form, tautomeric form is included in the scope of the present invention.
The present invention also partly relates to all salt of formula (I) compound.The salt of compound can be favourable, and this is the feature due to one or more salt, for example, under differing temps and humidity, improves medicine stability, or has desirable solubleness in water or in other solvent.For example, if give patient's salt (, using to form with external environment to contrast), the salt that preferably this salt is pharmaceutically useful and/or physiology is compatible.The term " pharmaceutically acceptable " using as adjective in present patent application refers to that modified noun is suitable for use as medicament production or as the part of medicament production.Pharmacologically acceptable salt comprises the salt that is generally used for forming an alkali metal salt, and is used to form the salt of the additive salt of free acid or free alkali.Conventionally, these salt typically can utilize ordinary method preparation, for example, by suitable acid or alkali, react with compound of the present invention.
The pharmaceutically acceptable acid additive salt of formula (I) compound can be prepared by inorganic or organic acid.The example of normally suitable mineral acid comprises: hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, nitric acid, carbonic acid, sulfuric acid and phosphoric acid.Suitable organic acid generally includes: for example, and other organic acid of aliphatics, cyclic aliphatic, aromatics, aromatic yl aliphat, heterocycle, carboxylic acid and sulphonic acids.Normally suitable organic acid object lesson comprises: acetic acid, trifluoroacetic acid, formic acid, propionic acid, succsinic acid, hydroxyethanoic acid, glyconic acid, didextrose acid, lactic acid, oxysuccinic acid, tartrate, citric acid, xitix, glucuronic acid, toxilic acid, fumaric acid, pyruvic acid, aspartic acid, L-glutamic acid, phenylformic acid, anthranilic acid, methylsulfonic acid, stearic acid, Whitfield's ointment, P-hydroxybenzoic acid, toluylic acid, mandelic acid, pamoic acid, ethyl sulfonic acid, Phenylsulfonic acid, pantothenic acid, 2-ethylenehydrinsulfonic acid, sulfanilic acid, cyclohexyl thionamic acid, Lalgine, β-hydroxybutyric acid, tetrahydroxyadipic acid, galacturonic acid, hexanodioic acid, Lalgine, heavy sulfuric acid, butyric acid, dextrocamphoric acid, camphorsulfonic acid, pentamethylene propionic acid, dodecyl sulphate, glycerine enanthic acid (glycoheptanoate), Phosphoric acid glycerol esters (glycerophosphate), enanthic acid, caproic acid, nicotinic acid, oxalic acid, palmitinic acid, pectinic acid, 2-naphthene sulfonic acid, 3-phenylpropionic acid, picric acid, PIVALIC ACID CRUDE (25), thiocyanic acid, the salt that toluenesulphonic acids becomes with undecanoic acid.
The pharmaceutically acceptable base addition salt of formula (I) compound comprises, for example, and metal-salt and organic salt.Preferred metal-salt comprises: basic metal (Ia family) salt, alkaline-earth metal (IIa family) salt and the acceptable metal-salt of other physiology.This salt can be prepared by aluminium, calcium, lithium, magnesium, potassium, sodium and zinc.Preferred organic salt can be prepared by amine, for example, and tromethane, diethylamine, N, N'-dibenzyl-ethylenediamin, chloroprocaine, choline, diethanolamine, quadrol, meglumine (N-meglumine) and PROCAINE HCL, PHARMA GRADE.Can be with following reagent, alkaline nitrogen-containing group is quaternized: for example, low alkyl group (C 1-C 6) halogen (for example, methyl, ethyl, propyl group and Butyryl Chloride, bromine and iodide), sulfuric acid dialkyl (for example, sulfuric acid dimethyl, diethyl, dibutyl and diamyl ester), long-chain halogenide (for example, the chlorine of decyl, lauryl, tetradecyl and stearyl, bromine and iodide), aralkyl halogen is (for example, benzyl and phenethyl bromide), and other reagent.
Formula (I) compound (with its salt) of any purity level (comprising pure and mild substantially pure) is within applicant's invention scope.About compound/salt/isomer, term " substantially pure " refers to: the preparation/composition that contains this compound/salt/isomer comprises this compound/salt/isomer that surpasses about 85% weight, preferably, this the compound/salt/isomer that surpasses about 90% weight, preferably, surpasses this compound/salt/isomer of about 95% weight, preferably, this the compound/salt/isomer that surpasses about 97% weight, and preferably, surpass this compound/salt/isomer of about 99% weight.
the preparation of compound
Can prepare compound of the present invention by synthetic chemistry method, provide the example herein.Be appreciated that the step order that can change in the method, reagent, solvent and reaction conditions can replace those reagent, solvent and the reaction conditions of specifically stating, and can be as required by susceptible part protection and deprotection.
The protecting group of C (O) OH part is including, but not limited to acetoxy-methyl, allyl group, benzoyl methyl, benzyl, benzyloxymethyl, the tertiary butyl, t-butyldiphenylsilyl, diphenyl-methyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropyl, Biphenylmethyl silyl, ethyl, to methoxybenzyl, methoxymethyl, methoxy ethoxy methyl, methyl, methyl thiomethyl, naphthyl, to nitrobenzyl, phenyl, n-propyl, 2, 2, 2-tri-chloroethyls, triethylsilyl, 2-(trimethyl silyl) ethyl, 2-(trimethyl silyl) ethoxyl methyl, trityl, etc..
The protecting group of C (O) and C (O) H part including, but not limited to: 1; 3-dioxy base ketal (1; 3-dioxylketal), diethyl ketal (diethylketal), dimethyl ketal (dimethylketal); 1; 3-dithian base ketal (1,3-dithianylketal), O-methyloxime; O-phenyl oxime, etc.
The protecting group of NH part is including, but not limited to ethanoyl, alanyl, benzoyl; benzyl (phenyl methyl), benzylidene, carbobenzoxy-(Cbz) (Cbz); tertbutyloxycarbonyl (Boc), 3,4-dimethoxy-benzyloxycarbonyl; diphenyl-methyl, diphenylphosphine acyl group, formyl radical; methylsulfonyl, to methoxyl group benzyloxy carbonyl, phenylacetyl; phthaloyl; succinyl, trichloro-ethoxycarbonyl, triethylsilyl; trifluoroacetyl group; trimethyl silyl, trityl, triphenyl silyl; p-toluenesulfonyl, etc.
The protecting group of OH and SH part is including, but not limited to ethanoyl, allyl group, allyloxy carbonyl, carbobenzoxy-(Cbz) (Cbz), benzoyl, benzyl, the tertiary butyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, 3, 4-dimethoxy-benzyl, 3, 4-dimethoxy-benzyloxycarbonyl, 1, 1-dimethyl-2-propenyl, diphenyl-methyl, formyl radical, methylsulfonyl, methoxyl group ethanoyl, 4-methoxyl group benzyloxy carbonyl, to methoxybenzyl, methoxycarbonyl, methyl, p-toluenesulfonyl, 2, 2, 2-trichloro-ethoxycarbonyl, 2, 2, 2-tri-chloroethyls, triethylsilyl, trifluoroacetyl group, 2-(trimethyl silyl) ethoxycarbonyl, 2-trimethyl silyl ethyl, trityl, 2-(triphenyl phosphorus base) ethoxycarbonyl, etc..
Reaction scheme
Figure DEST_PATH_IMAGE049
　　。
As shown in reaction scheme 1, can make 4-amino-2-(methylthio group) pyrimidine-5-ethyl formate (as described in US 2005/0020590 preparation) and alkali (such as, but be not limited to: sodium hydride) react, then with the compound of formula (1) (R wherein 1react as described herein), the compound of formula (2) is provided.This reaction generally at low temperatures, in solvent, carry out, such as, but be not limited to DMF.Alkali (such as, but be not limited to: under existence DIPEA), can make compound and the phosphorus oxychloride reaction of formula (2), the compound of formula (3) is provided.At high temperature, can make 2,2-dimethoxy-ethylamine react with the compound of formula (3), the compound of formula (4) is provided.This reaction is generally carried out in solvent, such as, but be not limited to: acetonitrile.The compound that can make formula (4) and acid (such as, but be not limited to: concentrated hydrochloric acid) react, the compound of formula (5) is provided.This reaction generally at high temperature, solvent (such as, but be not limited to: acetonitrile), carry out, and can in single mold microwave stove, carry out.Compound that can through type (5) and metachloroperbenzoic acid react the compound of preparation formula (6).This reaction generally at ambient temperature, in solvent, carry out, such as, but be not limited to methylene dichloride.Can make the compound of formula (6) and the compound of formula (7) (R wherein 4react as described herein), the compound of formula (8) is provided, it is representational the compounds of this invention.This reaction is generally at high temperature carried out, and can use solvent.
Figure 865059DEST_PATH_IMAGE050
Can make the compound (R wherein of formula (3) 1react with formyl hydrazine as described herein), the compound of formula (9) is provided.This reaction generally solvent (such as, but be not limited to: acetonitrile), at high temperature carry out.In addition, this reaction is carried out carrying out in microwave oven.Can make the compound of formula (9) react with metachloroperbenzoic acid, the compound of formula (10) is provided.This reaction generally at ambient temperature, in solvent, carry out, such as, but be not limited to methylene dichloride.Can make the compound of formula (10) and the compound of formula (7) (R wherein 4react as described herein), the compound of formula (11) is provided, it is representational the compounds of this invention.This reaction is generally at high temperature carried out, and can use solvent.
As shown in reaction scheme 3, can make the compound (R wherein of formula (3) 1the compound of formula (12) is provided as described herein) and reaction of sodium azide.This reaction generally at high temperature, in solvent, carry out, such as, but be not limited to DMF.Can make the compound of formula (12) react with metachloroperbenzoic acid, the compound of formula (13) is provided.This reaction generally at ambient temperature, in solvent, carry out, such as, but be not limited to methylene dichloride.Can make the compound of formula (13) and the compound of formula (7) (R wherein 4react as described herein), the compound of formula (14) is provided, it is representational the compounds of this invention.This reaction is generally at high temperature carried out, and can use solvent.
composition
In yet another aspect, the invention provides pharmaceutical composition, for regulating the kinase activity of humans and animals, it typically comprises compound and pharmaceutically acceptable carrier of formula (I).
Formula (I) compound can be used following manner administration: for example, through cheek, eye, oral, infiltration, parenteral (intramuscular, intraperitoneal, in breastbone, intravenously, subcutaneous), rectum, part, transdermal, vagina and intra-arterial, and intra-articular injection, in transfusion and body, place, for example, in vascular system, place.
Formula (I) compound can administration under the condition of using or do not use vehicle.Vehicle including, but not limited to, encapsulated agent (encapsulators) and additive be absorption enhancer for example, antioxidant, tackiness agent, buffer reagent, coating agent, tinting material, thinner, disintegrating agent, emulsifying agent, expands agent (extenders), filler, seasonings, wetting Agent for Printing Inks, lubricant, spices, sanitas, casting charge, release agent, sterilant, sweeting agent, solubilizing agent, wetting agent, its mixture etc.
For the preparation of the vehicle of the composition that contains formula (I) compound of oral administration including, but not limited to agar, Lalgine, aluminium hydroxide, phenylcarbinol, peruscabin, 1, 3-butyleneglycol, carbomer, Viscotrol C, Mierocrystalline cellulose, cellulose acetate, theobroma oil, W-Gum, Semen Maydis oil, Oleum Gossypii semen, Crospovidone, triglyceride, ethanol, ethyl cellulose, Laurate ethyl, ethyl oleate, fatty acid ester, gelatin, germ oil, glucose, glycerine, peanut oil, HYDROXY PROPYL METHYLCELLULOSE, Virahol, isotonic saline solution, lactose, magnesium hydroxide, Magnesium Stearate, Fructus Hordei Germinatus, mannitol, monoglyceride, sweet oil, peanut oil, potassium phosphate salt, yam starch, polyvidone, propylene glycol, Ringer's solution, Thistle oil, sesame oil, Xylo-Mucine, sodium phosphate salt, Sodium Lauryl Sulphate BP/USP, sorbose sodium alkoxide, soybean oil, stearic acid, stearoyl-fumarate salt, sucrose, tensio-active agent, talcum powder, tragacanth, tetrahydrofurfuryl alcohol, triglyceride level, water, with its mixture, etc..For the preparation of the vehicle of the composition that contains formula (I) compound of eye or oral administration including, but not limited to 1,3 butylene glycol, Viscotrol C, Semen Maydis oil, Oleum Gossypii semen, ethanol, the fatty acid ester of sorbitan, germ oil, peanut oil, glycerine, Virahol, sweet oil, polyoxyethylene glycol, propylene glycol, sesame oil, water, and its mixture, etc.For the preparation of the vehicle of the composition that contains formula (I) compound of infiltration administration including, but not limited to Chlorofluorocarbons (CFCs), ethanol, water, its mixture, etc.For the preparation of the vehicle of the composition that contains formula (I) compound of parenteral admin including, but not limited to 1,3 butylene glycol, Viscotrol C, Semen Maydis oil, Oleum Gossypii semen, glucose, germ oil, peanut oil, liposome, oleic acid, sweet oil, peanut oil, Ringer's solution, Thistle oil, sesame oil, soybean oil, U.S.P. or isotonic sodium chlorrde solution, water, its mixture, etc.For the preparation of the vehicle of the composition that contains formula (I) compound of rectum or vagina administration including, but not limited to theobroma oil, polyoxyethylene glycol, paraffin, its mixture, etc.
Pharmaceutical composition of the present invention and method can further comprise other therapeutical active compound mentioned in this article, and this active compound is generally used for treating above-mentioned pathological disorders.
using method
In yet another aspect, the invention provides the method for the treatment of or preventing mammiferous disease or illness with compound of the present invention or composition, this disease or illness are with kinase whose adjusting, overexpression or lack of proper care relevant.Especially, expect that compound of the present invention can be used for treating disease or illness, during this disease or illness, protein kinase (for example, any or all wee-1 family member) be expressed.
In one group of embodiment, can be by the people of kinase whose inhibitor for treating or the disease of other animal and illness including, but not limited to acoustic tumor, acute leukemia, acute lymphoblastic leukemia, acute myelocytic leukemia (monocyte, myeloblast, malignant adenoma, angiosarcoma, astrocytoma, Myelomonocyte and promyelocyte), acute T chronic myeloid leukemia, rodent cancer, cholangiocarcinoma, bladder cancer, the cancer of the brain, mammary cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, lymphocytic leukemia, chronic myelocytic (granulocyte) leukemia, chronic myelocytic leukemia, colorectal carcinoma, colorectal carcinoma, craniopharyngioma, cystadenocarcinoma, diffuse large B cell lymphoma, proliferative abnormality (dysproliferative) changes (heteroplasia and metaplasia), embryonal carcinoma, carcinoma of endometrium, endotheliosarcoma, ependymoma, epithelial cancer, erythroleukemia, esophagus cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, sexual cell carcinoma of testis, glioma, heavy chain disease, hemangioblastoma, liver cancer, hepatocellular carcinoma, the insensitive prostate cancer of hormone, leiomyosarcoma, liposarcoma, lung cancer, lymphangioendothelial sarcoma, lymphangiosarcoma, Lymphocytic leukemia, lymphoma (Huo Qijin and non-Hodgkin lymphoma), bladder, breast, colon, lung, ovary, pancreas, prostate gland, the malignant tumour in skin and uterus and high proliferation illness, the lymph malignant tumour of T cell or B cell source, leukemia, lymphoma, medullary carcinoma, myeloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelocytic leukemia, myelomatosis, myxosarcoma, neuroblastoma, nonsmall-cell lung cancer, oligodendroglioma, oral carcinoma, osteogenic sarcoma, ovarian cancer, carcinoma of the pancreas, papillary carcinoma, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, the rectum cancer, renal cell carcinoma, retinoblastoma, rhabdosarcoma, sarcoma, sebaceous carcinoma, spermocytoma, skin carcinoma, small cell lung cancer, essence solid tumor (cancer and sarcoma), small cell lung cancer, cancer of the stomach, squamous cell carcinoma, synovioma, syringocarcinoma, thyroid carcinoma, Waldenstr m ' s macroglobulinemia, tumor of testis, uterus carcinoma and Wilms' tumour.
In one group of embodiment, can be by the people of kinase whose inhibitor for treating or the disease of other animal and illness including, but not limited to the defective tumour of p53 albumen.P53 albumen is by the tumor suppressor protein of TP53 genes encoding in the mankind.P53 albumen regulates the cell cycle, and therefore plays the effect of the tumor inhibitor that relates to preventing cancer.Suppress Wee1 kinases, can make tumour cell disturb sensitivity to DNA damage and/or cell cycle, especially because p53 protein delation is lost G 1those tumours of-phase check point.
How the forfeiture of expressing about Wee1 and it relate to the discussion of p53 protein delation, can Annual Review of Biochemistry (2004, find in 73:39-85).
About p53 transgenation and human tumor type, can Nature (1989, obtain in 342:705-708).
About the discussion of Wee1 kinases and the defective tumour cell of p53, can Molecular Cancer Therapy (2009, obtain in 8:11).
About the discussion of p53 and Wee1 kinases and anticancer therapy, can BMC Cancer (2006, obtain in 6:292).
About the discussion of Wee1 kinases and the defective tumour cell of p53, can Current Clinical Pharmacology (2010, obtain in 5:186-191).
Method of the present invention typically comprises the compound of the formula (I) of the patient's significant quantity that needs treatment.The treatment significant quantity of formula (I) compound depends on the recipient for the treatment of, the disease for the treatment of and its severity, the composition that comprises it, administration time, route of administration, treatment phase length, usefulness, Cl and whether jointly give other medicines.For the preparation of the quantity that gives formula (I) compound of patient's composition with single dose or separate doses form every day, be about 0.03 to about 200 mg/kg body weight.Unit-dose composition contains these quantity or its array configuration of approximately measuring.
combination therapy
The present invention further provides the method for the coupling form of using compound of the present invention or composition and one or more other promoting agent.
When formula (I) compound is used together with following, expectation formula (I) compound is effective: alkylating agent, angiogenesis inhibitor, antibody, metabolic antagonist, antimitotic agent, antiproliferative, antiviral agent, aurora kinase inhibitors, apoptosis promotor (for example, Bcl-xL, Bcl-w and Bfl-1) inhibitor, the activator of death receptor pathway *, Bcr-Abl kinase inhibitor, BiTE (dual specific T Conjugation device) antibody, antibody-drug conjugate, biological response modifier, the kinase inhibitor of cyclin dependent, cell cycle inhibitor, cyclooxygenase-2 inhibitor, DVD, leukosis virus oncogene homologue (ErbB2) acceptor inhibitor, growth factor receptor inhibitors, heat shock protein(HSP) (HSP)-90 inhibitor, histone deacetylase (HDAC) inhibitor, hormonotherapy, immunity, the inhibitor of the inhibitor of apoptosis albumen (IAP), insert microbiotic, kinase inhibitor, kinesin inhibitor, Jak2 inhibitor, the Mammals target of rapamycin inhibitor, microRNA's, the extracellular signal-regulated kinase inhibitor of mitogen-activation, multivalent binding proteins, nonsteroidal anti-inflammatory drug (NSAID), poly--ADP (adenosine diphosphate (ADP))-ribose polymerase (PARP) inhibitor, platinum chemotherapeutics, polo class (polo-like) kinases (Plk) inhibitor, phosphoinositide-3 kinases (PI3K) inhibitor, proteoplast inhibitor, purine analogue, pyrimidine analogue, receptor tyrosine kinase inhibitors, retinoid/triangle (deltoids) plant alkaloid, small molecules suppresses ribonucleic (siRNA), topoisomerase enzyme inhibitor, ubiquitin ligase inhibitor, etc., coupling form with one or more medicament with these medicaments.
BiTE antibody is two special antibody, and it is by guide T cell to remove to attack cancer cells with two Cell bindings simultaneously.Then T cell is attacked target cancer cell.The example of BiTE antibody comprises: A De wood monoclonal antibody (adecatumumab) (Micromet MT201), blinatumomab (Micromet MT103) etc.Without being limited by theory, T cell causes that one of mechanism of target cancer cell apoptosis is by the exocytosis of cytolytic granule component, and it comprises pore-forming protein and granzyme B.In this respect, shown can the decay apoptosis of pore-forming protein and granzyme B induction of Bcl-2.These data declarations the cytotoxin effect that caused by T cell can improve target cancer cell time of the restraining effect of Bcl-2 (V.R. Sutton, D.L. Vaux and J.A. Trapani, j. of Immunology 1997, 158 (12), 5783).
SiRNA has endogenous RNA base or the molecule of the Nucleotide chemically modified.This modification can not eliminated cytoactive, but gives the stability of increase and/or the usefulness of increase cell.The example of chemically modified comprises phosphorothionate group, and 2'-deoxynucleotide, contains 2'-OCH 3-ribonucleotide, 2'-F-ribonucleotide, 2'-methoxy ethyl ribonucleotide, its combination etc.SiRNA can the vicissitudinous length of tool (for example, 10-200 bps) and structure (for example, hair clip shape thing, list/two strands, projection, recessed gap/gaps, dislocation), and in cell processing to provide active gene reticent.Two-chain siRNA (dsRNA) has identical Nucleotide number on each chain (blunt end) or asymmetric end (overhang).The overhang of 1-2 Nucleotide can exist on justice and/or antisense strand, and exists on the 5'-of given chain and/or 3'-end.
Multivalent binding proteins is the combination albumen that comprises two or more antigen binding sites.Multivalent binding proteins can be engineered to and have three or more antigen site, it is not naturally occurring antibody conventionally.Term " polyspecific is in conjunction with albumen " refers to can be in conjunction with the combination albumen of two or more relevant or irrelevant targets.Dual variable territory (DVD) is the combination albumen that comprises tetravalence or the multivalence of two or more antigen binding sites in conjunction with albumen.Such DVDs can be monospecific (that is, can in conjunction with an antigen) or polyspecific (that is, can in conjunction with two or more antigen).The DVD that comprises two heavy chain DVD polypeptide and two light chain DVD polypeptide is called as DVD Ig's in conjunction with albumen.Often half comprises a heavy chain DVD polypeptide, a light chain DVD polypeptide and two antigen binding sites to DVD Ig.Each binding site comprises a heavy chain variable domain and a light chain variable territory, and each antigen binding site has 6 CDRs that participate in antigen combination altogether.Polyspecific DVD comprises that DVD in conjunction with DLL4 and VEGF is in conjunction with albumen, or C-met and EFGR, or ErbB3 and EGFR.
Alkylating agent comprises altretamine, AMD-473, AP-5280, apaziquone, bendamustine, brostallicin, busulfan, carboquone, carmustine (BCNU), Chlorambucil, CLORETAZINE (Rameau department spit of fland, VNP 40101M), endoxan, Decloxizine, estramustine, fotemustine, Glufosfamide, ifosfamide, KW-2170, lomustine (CCNU), Mafosfamide (mafosfamide), melphalan, mitobronitol, mitolactol, Nidran, mustargen N oxide compound, ranomustine (Ranimustine), Temozolomide, thiotepa, TREANDA (bendamustine), Treosulfan (treosulfan), rofosfamide etc.
Angiogenesis inhibitor comprises: endothelium-special receptor tyrosine kinase (Tie-2) inhibitor, EGF-R ELISA (EGFR) inhibitor, insulin-like growth factor-2 acceptor (IGFR-2) inhibitor, MMP-2 (MMP-2) inhibitor, Matrix Metalloproteinase-9 (MMP-9) inhibitor, PDGF acceptor (PDGFR) inhibitor, thrombostondin analogue, vascular endothelial growth factor receptor Tyrosylprotein kinase (VEGFR) inhibitor etc.
Metabolic antagonist comprises: ALIMTA (training U.S. bent azoles (Pemetrexed) disodium, LY231514, MTA), 5-azacitidine, XELODA (capecitabine), carmofur, LEUSTAT (CldAdo), Clofarex, cytosine arabinoside, Cytarabine ocfosfate, cytarabin, Decitabine, Deferoxamine, doxifluridine, eflornithine, EICAR (5-ethynyl-1-β-D-RIBOSE base imidazoles-4-methane amide), enocitabine, ethnylcytidine, fludarabine, separately or with the 5 FU 5 fluorouracil of folinic acid coupling, GEMZAR (gemcitabine), hydroxyurea, ALKERAN (melphalan), purinethol, Ismipur ribonucleoside, methotrexate, mycophenolic acid, Nelzarabine (nelarabine), Nola Qu Te (nolatrexed), octadecyl sodium phosphate, pyrrole profit bent rope (pelitrexol), pentostatin, Raltitrexed (raltitrexed), ribavirin, triapine, trimetrexate, S-1, thiazole furan quinoline, Tegafur, TS-1, vidarabine, UFT etc.
Antiviral agent comprises ritonavir, hydroxychloroquine etc.
Aurora kinase inhibitors comprises ABT-348, AZD-1152, and MLN-8054, VX-680, aurora A-specificity kinase inhibitor, aurora B-specificity kinase inhibitor and general aurora kinase inhibitors, etc.
Bcl-2 protein inhibitor comprises: AT-101 ((-) gossypol), GENASENSE (G3139 or Ao Limosen (oblimersen) (Bcl-2-target antisense oligonucleotide)), IPI-194, IPI-565, N-(4-(4-((4'-chlorine (1, 1'-biphenyl)-2-yl) methyl) piperazine-1-yl) benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenyl sulfenyl) methyl) propyl group) amino)-3-nitrobenzene sulfonamide) (ABT-737), N-(4-(4-((2-(4-chloro-phenyl-)-5, 5-dimethyl-1-hexamethylene-1-alkene-1-yl) methyl) piperazine-1-yl) benzoyl)-4-(((1R)-3-(morpholine-4-yl)-1-((phenyl sulfenyl) methyl) propyl group) amino)-3-((trifluoromethyl) alkylsulfonyl) benzsulfamide (ABT-263), GX-070 (obatoclax) etc.
Bcr-Abl kinase inhibitor comprises: DASATINIB (BMS-354825), GLEEVEC (imatinib) etc.
CDK inhibitor comprises: AZD-5438, BMI-1040, BMS-032, BMS-387, CVT-2584, Flavopiridol (flavopyridol), GPC-286199, MCS-5A, PD0332991, PHA-690509, seliciclib (CYC-202, R-roscovitine), ZK-304709 etc.
Cox 2 inhibitor comprises: ABT-963, ARCOXIA (Etoricoxib), BEXTRA (valdecoxib), BMS347070, CELEBREX (celecoxib), COX-189 (lumiracoxib (lumiracoxib)), CT-3, DERAMAXX (SC 59046 (deracoxib)), JTE-522,4-methyl-2-(3; 4-3,5-dimethylphenyl)-1-(4-sulfamyl phenyl-1H-pyrroles), MK-663 (Etoricoxib), NS-398; Pa Ruikao battalion; RS-57067, SC-58125, SD-8381; SVT-2016; S-2474, T-614, VIOXX (rofecoxib) etc.
EGFR inhibitor comprises: ABX-EGF, anti-EGFR immunoliposome, EGF-vaccine, EMD-7200, ERBITUX (Cetuximab), HR3, IgA antibody, IRESSA (Gefitinib), TARCEVA (erlotinib or OSI-774), TP-38, EGFR fusion rotein, TYKERB (lapatinibditosylate (lapatinib)) etc.
ErbB2 acceptor inhibitor comprises: CP-724-714, CI-1033 (OK a karaoke club is for Buddhist nun (canertinib)), HERCEPTIN (Herceptin), TYKERB (lapatinibditosylate (lapatinib)), OMNITARG (2C4, handkerchief trastuzumab (petuzumab)), TAK-165, GW-572016 (ionafarnib), GW-282974, EKB-569, PI-166, dHER2 (HER2 vaccine), APC-8024 (HER-2 vaccine), anti-HER/2neu bi-specific antibody, B7.HER2IgG3, AS HER2 trifunctional bi-specific antibody, mAB AR-209, mAB 2B-1 etc.
Histone deacetylase inhibitors comprises: depsipeptide, LAQ-824, MS-275, Top pungent (trapoxin), Vorinostat (SAHA), TSA, valproic acid etc.
HSP-90 inhibitor comprises: 17-AAG-nab, 17-AAG, CNF-101, CNF-1010, CNF-2024,17-DMAG, geldanamycin, IPI-504, KOS-953, MYCOGRAB (people's recombinant antibody of HSP-90), NCS-683664, PU24FCl, PU-3, radicicol, SNX-2112, STA-9090 VER49009 etc.
The inhibitor of apoptosis albumen comprises: HGS1029, GDC-0145, GDC-0152, LCL-161, LBW-242 etc.
Antibody-drug conjugate comprises: anti-CD22-MC-MMAF, anti-CD22-MC-MMAE, anti-CD22-MCC-DM1, CR-011-vcMMAE, PSMA-ADC, MEDI-547, SGN-19Am SGN-35, SGN-75 etc.
The activator of death receptor pathway * comprises: TRAIL, antibody or other medicament of target TRAIL or death receptor (for example DR4 and DR5), Apomab for example, conatumumab, ETR2-ST01, GDC0145 (carrying out husky wooden monoclonal antibody (lexatumumab)), HGS-1029, LBY-135, PRO-1762 and Herceptin.
Kinesin inhibitor comprises: Eg5 inhibitor, AZD4877 for example, ARRY-520; CENPE inhibitor, for example GSK923295A etc.
JAK-2 inhibitor comprises: CEP-701 (lesaurtinib), XL019 and INCB018424 etc.
Mek inhibitor comprises: ARRY-142886, ARRY-438162, PD-325901, PD-98059 etc.
MTOR inhibitors comprises: AP-23573, and CCI-779, everolimus, RAD-001, rapamycin, sirolimus (temsirolimus), the emulative TORC1/TORC2 inhibitor of ATP, comprises PI-103, PP242, PP30, Torin 1, etc.
The medicine of non-steroidal anti-inflammatory disease comprises: AMIGESIC (salsalate), DOLOBID (diflunisal), MOTRIN (Ibuprofen BP/EP), ORUDIS (Ketoprofen), RELAFEN (nabumetone), FELDENE (piroxicam), Ibuprofen cream agent, ALEVE (Naproxen Base) and NAPROSYN (Naproxen Base), VOLTAREN (diclofenac), INDOCIN (INDOMETHACIN), CLINORIL (sulindac), TOLECTIN (TOL), LODINE (R-ETODOLAC), TORADOL (ketorolac), DAYPRO (Taisho)) etc.
PDGFR inhibitor comprises: C-451, and CP-673, CP-868596, etc.
Platinum chemotherapeutics comprises: cis-platinum, ELOXATIN (oxaliplatin), eptaplatin, Lobaplatin, S 254, PARAPLATIN (carboplatin), Satraplatin, JM473 etc.
Polo class (Polo-like) kinase inhibitor comprises BI-2536 etc.
Phosphoinositide-3 kinases (PI3K) inhibitor comprises: wortmannin, LY294002, XL-147, CAL-120, ONC-21, AEZS-127, ETP-45658, PX-866, GDC-0941, BGT226, BEZ235, XL765 etc.
Thrombostondin analogue comprises: ABT-510, ABT-567, ABT-898, TSP-1 etc.
VEGFR inhibitor comprises: AVASTIN (rhuMAb-VEGF), ABT-869, AEE-788, ANGIOZYME (ribozyme (Ribozyme Pharmaceuticals (the Boulder that suppresses vasculogenesis, CO.) and Chiron (Emeryville, CA)), Axitinib (AG-13736), AZD-2171, CP-547,632, IM-862, MACUGEN (piperazine Jia Tani (pegaptamib)), NEXAVAR (Xarelto (sorafenib), BAY43-9006), pazopanib (pazopanib) (GW-786034), PTK787 (vatalanib) (PTK-787, ZK-222584), SUTENT (Sutent (Sunitinib), SU-11248), VEGF trap, ZACTIMA (ZD6474 (vandetanib), ZD-6474), GA101, ofatumumab, ABT-806 (mAb-806), ErbB3 specific antibody, BSG2 specific antibody, DLL4 specific antibody and C-met specific antibody, etc.
Microbiotic comprises: insert microbiotic, aclarubicin for example, dactinomycin, amrubicin, anthracycline (annamycin), Dx, BLENOXANE (bleomycin), daunorubicin, CAELYX or MYOCET (liposome Dx), elsamitrucin, pidorubicin (epirbucin), glarbuicin, ZAVEDOS (idarubicin), ametycin, Nemorubicin, neocarzinostatin, Peplomycin Sulfate, pirarubicin, butterfly mycin (rebeccamycin), zinostatin (stimalamer), U-9889, VALSTAR (valrubicin (valrubicin)), neocarzinostatin etc.
Topoisomerase enzyme inhibitor comprises: aclarubicin, 9-aminocamptothecin, amonafide, amsacrine, becatecarin, Belotecan (belotecan), BN-80915, CAMPTOSAR (Rinotecan hydrochloride), camptothecine, CARDIOXANE (ADR-529 (dexrazoxine)), Diflomotecan (diflomotecan), Yi Duodi card woods (edotecarin), ELLENCE or PHARMORUBICIN (epirubicin), Etoposide, exatecan (exatecan), 10-hydroxycamptothecine, gefitinib, lurtotecan, mitoxantrone, rubitecan (orathecin), pirarubicin (pirarbucin), China fir fine jade (pixantrone), Rubitecan, sobuzoxane, SN-38, tafluposide, Hycamtin etc.
Antibody comprises: AVASTIN (rhuMAb-VEGF), CD40-specific antibody, chTNT-1/B, ground promise monoclonal antibody (denosumab), ERBITUX (Cetuximab), HUMAX-CD4 (zanolimumab), IGF1R-specific antibody, lintuzumab, PANOREX (Edrecolomab), RENCAREX (WX G250), RITUXAN (Mabthera), ticilimumab, trastuzimab, I type and II type CD20 antibody, etc.
Hormonotherapy comprises: ARIMIDEX (Anastrozole), AROMASIN (Exemestane), arzoxifene, CASODEX (bicalutamide), CETROTIDE (cetrorelix), ground lid Rayleigh (degarelix), deslorelin, DESOPAN (Win-24540), dexamethasone, DROGENIL (flutamide), EVISTA (Raloxifene), AFEMA (method is bent azoles), FARESTON (toremifene), FASLODEX (fulvestrant), FEMARA (letrozole), formestane, glucocorticosteroid, HECTOROL (doxercalciferol (doxercalciferol)), RENAGEL (2-Propen-1-amine polymer with(chloromethyl)oxirane carbonate (sevelamer)), Lasofoxifene, TAP-144, MEGACE (megestrol), MIFEPREX (Mifepristone), NILANDRON (Nilutamide), NOLVADEX (tamoxifen citrate), PLENAXIS (Ah times's Rake (abarelix)), prednisone, PROPECIA (finasteride), rilostane, SUPREFACT (buserelin), TRELSTAR (luteinizing hormone releasing hormone (LHRH)), VANTAS (histrelin (histrelin) implant), VETORYL (Win-24540 or modrastane), ZOLADEX (fosrelin, goserelin) etc.
Deltoids and retinoid comprise: seocalcitol () (EB1089, CB1093), lexacalcitrol (KH1060), fenretinide (fenretinide), PANRETIN (aliretinoin), ATRAGEN (liposome vitamin A acid), TARGRETIN (bexarotene (bexarotene)), LGD-1550 etc.
PARP inhibitor comprises: ABT-888 (veliparib), Aura handkerchief Buddhist nun (olaparib), KU-59436, AZD-2281, AG-014699, BSI-201, BGP-15, INO-1001, ONO-2231 etc.
Plant alkaloid is including, but not limited to vincristin, vinealeucoblastine(VLB), desacetyl vinblastine amide, Vinorelbine etc.
Proteasome inhibitor comprises: VELCADE (Velcade (bortezomib)), MG132, NPI-0052, PR-171 etc.
The example of immunoreagent comprises Interferon, rabbit and other immunity-raising reagent.Interferon, rabbit comprises: interferon alpha, Intederon Alpha-2a, Interferon Alpha-2b, interferon beta, interferon-gamma-1a, ACTIMMUNE (gamma interferon 1-b), interferon-gamma-n1, its coupling form, etc.Other medicament comprises ALFAFERONE (iFN-α), BAM-002 (Sleep-promoting factor B), BEROMUN (tasonermin (tasonermin)), BEXXAR (tositumomab (tositumomab)), CAMPATH (alemtuzumab (alemtuzumab)), CTLA4 (cytotoxin lymphocyte antigen 4), Decloxizine, denileukin (denileukin), epratuzumab, GRANOCYTE (lenograstim), lentinan, white corpuscle interferon-alpha, Imiquimod, MDX-010 (anti-CTLA-4), Melacine, mitumomab (mitumomab), Sch-39300, MYLOTARG (lucky trastuzumab azoles rice star (gemtuzumab ozogamicin) difficult to understand), NEUPOGEN (filgrastim), OncoVAC-CL, OVAREX (Ao Gefu monoclonal antibody (oregovomab)), pemtumomab (Y-muHMFG1), PROVENGE (sipuleucel-T), sargaramostim, sizofiran, teceleukin (teceleukin), THERACYS (bacille Calmette-Guerin vaccine), ubenimex, VIRULIZIN (immunotherapeutic agent, Lorus Pharmaceuticals), Z-100 (material-specific of Maruyama (SSM)), WF-10 (tetrachloro ten oxide compounds (Tetrachlorodecaoxide) are (TCDO)), PROLEUKIN (rIL-2), ZADAXIN (Thymosin-Alpha1 (thymalfasin)), ZENAPAX (reach (gram) pearl monoclonal antibody), ZEVALIN (90Y-ibritumomab tiuxetan (ibritumomab tiuxetan)), etc.
Biological response modifier is to improve the defense mechanism of living organism or the medicament of biologically, for example histiocytic survival, growth or differentiation, make them there is anti-tumor activity, comprise Kerstin (krestin), lentinan, sizofiran, Picibanil (picibanil), PF-3512676 (CpG-8954), ubenimex etc.
Pyrimidine analogue comprises: cytosine arabinoside (ara C or Arabinoside C), cytarabin, doxifluridine, FLUDARA (fludarabine), 5-FU (5 FU 5 fluorouracil), azauridine, GEMZAR (gemcitabine), TOMUDEX (ratitrexed), TROXATYL (Triacetyluridine troxacitabine (troxacitabine)) etc.
Purine analogue comprises: LANVIS (Tioguanine) and PURI-NETHOL (purinethol).
Antimitotic agent comprises: Ba Tabulin (batabulin), epothilone d (KOS-862), N-(2-((4-hydroxy phenyl) amino) pyridin-3-yl)-4-methoxybenzenesulphoismide, ipsapirone (ixabepilone) (BMS-247550), Paclitaxel, TAXOTERE (docetaxel), PNU100940 (109881), ipsapirone (patupilone), XRP-9881 (La Luotasai (larotaxel)), Vinflunine, ZK-EPO (synthetic esperamicin) etc.
Ubiquitin ligase inhibitor comprises: MDM2 inhibitor, and nutlins for example, NEDD8 inhibitor, MLN4924 for example, etc.
Compound of the present invention can also be as the radiosensitizer that improves radiotherapeutic effect.The example of radiotherapy comprises: external beam radiotherapy, and deep therapy, brachytherapy and sealed source, unencapsulated source radiotherapy, etc.
In addition, formula (I) compound can with other chemotherapeutic coupling, ABRAXANE (ABI-007) for example, ABT-100 (farnesyl transferase inhibitor), ADVEXIN (Ad5CMV-p53 vaccine), ALTOCOR or MEVACOR (lovastatin), AMPLIGEN (the poly-C12U of poly-I-, synthetic RNA), APTOSYN (exisulind (exisulind)), AREDIA (pamidronic acid), arglabin, L-asparaginase, Atamestane (1-methyl-3,17-diketone-androstane-Isosorbide-5-Nitrae-diene), AVAGE (retinoic acid (tazarotene)), AVE-8062 (Combretastatin (combreastatin) derivative), BEC2 (mitumomab (mitumomab)), cachectin (cachectin) or cachexin (tumour necrosis factor), canvaxin (vaccine), CEAVAC (cancer vaccine), CELEUK (celmoleukin), CEPLENE (two hydrochloric acid groups are pressed), CERVARIX (Human-papilloma Vaccine), CHOP (C:CYTOXAN (endoxan); H:ADRIAMYCIN (hydroxyl Dx); O: vincristin (ONCOVIN ); P: prednisone), CYPAT (acetic acid Sai Pulong), combrestatin A4P, DAB (389) EGF (catalysis and the migration territory that connect the diphtheria toxin of base and human epidermal growth factor fusion by His-Ala) or TransMID-107R (diphtheria toxin), Dacarbazine, actinomycin, 5,6-dimethyl Oxoxanthone-4-acetic acid (DMXAA), eniluracil, EVIZON (squalamine (squalamine) lactic acid salt), DIMERICINE (T4N5 liposome lotion), discodermolide, DX-8951f (methylsulfonic acid exatecan (exatecan)), enzastaurin, EPO906 (epithilone B) GARDASIL (tetravalence human papillomavirus (6,11,16,18 type) recombiant vaccine), GASTRIMMUNE , GENASENSE , GMK (ganglioside conjugate vaccine), GVAX (carcinoma of prostate vaccine), halofuginone (halofuginone), histrelin (histerelin), hydroxyurea, according to class's phosphonic acids, IGN-101, IL-13-PE38, IL-13-PE38QQR (cintredekin besudotox), IL-13-Rhodopseudomonas extracellular toxin, interferon-' alpha ', interferon-γ, JUNOVAN or MEPACT (rice lumbering peptide (mifamurtide)), Luo Nafani (lonafarnib), 5,10-CH2-THFA, D-18506 (Hexadecylphosphocholine), NEOVASTAT (AE-941), NEUTREXIN (trimetrexate glucuronate), NIPENT (pentostatin), ONCONASE (rnase), ONCOPHAGE (Melacine treatment), ONCOVAX (IL-2 vaccine), ORATHECIN (Rubitecan), OSIDEM (cell drug based on antibody), OVAREX mAb (monoclonal antibody of mouse), Paclitaxel, PANDIMEX (comes from the aglycone saponin of ginseng, comprise 20 (S)-protopanaxadiols (aPPD) and 20 (S)-protopanaxatriols (aPPT)), Victibix (panitumumab), PANVAC -VF (Investigational cancer vaccine), Pegaspargase, PEG-IFN A, the appropriate Supreme Being's that of benzene (phenoxodiol), procarbazine, Rui Masita (rebimastat), REMOVAB (catumaxomab), REVLIMID (Revlimid (lenalidomide)), RSR 13 (Efaproxiral (efaproxiral)), SOMATULINE lA (Lanreotide), SORIATANE (Etretin), staurosporine (streptomyces staurospore), talabostat (PT100), TARGRETIN (bexarotene (bexarotene)), TAXOPREXIN (DHA-Paclitaxel), TELCYTA (canfosfamide, TLK286), temilifene, TEMODAR (Temozolomide), Tesmilifene (tesmilifene), reaction stops, THERATOPE (STn-KLH), thymitaq (2-amino-3,4-dihydro-6-methyl-4-oxo-5-(4-pyridyl sulfenyl) quinazoline dihydrochloride), TNFERADE (adenovirus carrier: the DNA vector of the gene that contains tumor necrosis factor-alpha),), TRACLEER or ZAVESCA (bosentan), vitamin A acid (Retin-A), sinomenine, TRISENOX (white arsenic), VIRULIZIN , ukrain (the alkaloidal derivative of pilewort plant), vitaxin (anti-alphavbeta3 antibody), XCYTRIN (motexafin (motexafin) gadolinium), XINLAY (atrasentan (atrasentan)), XYOTAX (PPX (paclitaxel poliglumex)), YONDELIS (ET-743 (trabectedin)), ZD-6126, ZINECARD (dexrazoxane), ZOMETA (Zoledronic acid), zorubicin etc.
Embodiment
Embodiment 1
6-(2-chloro-phenyl-)-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 1A
3-(2-chloro-phenyl-)-7-(methylthio group) Kui Linpyrimido quinoline [4,5-d] pyrimidine-2,4 (1H, 3H)-diketone
At 0 ℃, NaH (5.26 g, 131 mmol) is joined in DMF (700 mL) solution of 4-amino-2-(methylthio group) pyrimidine-5-ethyl formate (US 2005/0020590 for 20.0 g, 94 mmol).After 10 minutes, the chloro-2-isocyanato of 1-(isocyanato) benzene-(15.9 mL, 131 mmol) are dropwise joined in this mixture.This reaction is heated to room temperature, and stirs 6 hours.By this salt solution (200 mL) and water (1000 mL) dilution for reaction mixture, with ether (700 mL, 2x), extract.With 5% citric acid acidifying water layer (until pH=4-5), by brine treatment, by ethyl acetate (2x), extract.By organic layer water (2x) washing merging, use MgSO 4dry, filter, concentrated, remove most of solvent.Filter this mixture, and solid is washed with cold ethyl acetate, dry by bake oven, title compound is provided.
Embodiment 1B
The chloro-3-of 2-(2-chloro-phenyl-)-7-(methylthio group) Kui Linpyrimido quinoline [4,5-d] pyrimidine-4 (3H)-one
By embodiment 1A (15.9 g, 49.6 mmol), POCl 3the mixture of (55 mL, 590 mmol) and diisopropylethylamine (55 mL, 315 mmol) heats 1.5 hours at 90 ℃.Concentrated this reaction mixture.Resistates is used to ice and saturated NaHCO carefully 3process, then by ethyl acetate, extract.By being suspended in two insoluble substances in layer, filter, with ether and water washing, dry by bake oven, title compound is provided.Two layers in separating filtrate.By ethyl acetate, wash water layer.By the organic layer MgSO of merging 4dry, filter, concentrated, grind (twice) together with ethyl acetate/ether, extra title compound is provided.
Embodiment 1C
3-(2-chloro-phenyl-)-2-(2,2-dimethoxy-ethyl is amino)-7-(methylthio group) Kui Linpyrimido quinoline [4,5-d] pyrimidine-4 (3H)-one
The mixture of 2,2-dimethoxy-ethylamine (0.744 g, 7.08 mmol) and embodiment 1B (1.20 g, 3.54 mmol) and acetonitrile (20 mL) is heated 40 minutes at 80 ℃.Concentrated this mixture, uses NaHCO 3process, and extract by ethyl acetate (2x).Use MgSO 4the dry organic layer merging, filters, concentrated, and title compound is provided.
Embodiment 1D
4-(the chloro-phenyl of 2-)-8-methyl sulfenyl-4H-3,4,7,9,9b-pentaaza-cyclopenta [a] naphthalene-5-ketone
Embodiment 1C (0.558 g) is processed with dense HCl (0.10 mL) in acetonitrile (8 mL).By this mixture in Biotage microwave reactor, at 160 ℃, heat 15 minutes.Except desolventizing.By the saturated NaHCO of resistates 3process, and extract by ethyl acetate (2x).By the organic layer MgSO of merging 4dry, filter, concentrated, purifying on 40 g posts, is used ISCO Companion flash chromatographic system, uses CH 2cl 2/ ethyl acetate (4:6 to 3:7) wash-out, provides title compound.
Embodiment 1E
4-(the chloro-phenyl of 2-)-8-methanesulfinyl-4H-3,4,7,9,9b-pentaaza-cyclopenta [a] naphthalene-5-ketone
By metachloroperbenzoic acid (0.502 g, 2.24 mmol) and embodiment 1D (0.700 g, 2.04 mmol) at CH 2cl 2mixture in (40 mL) stirs 2 hours.Use CH 2cl 2dilute this reaction mixture, use saturated NaHCO 3the aqueous solution and saturated Na 2s 2o 3solution washing.Use MgSO 4dry organic layer, filters, concentrated, and title compound is provided.
Embodiment 1F
6-(2-chloro-phenyl-)-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
The mixture of embodiment 1E (45.0 mg, 0.125 mmol) and 4-(4-methylpiperazine-1-yl) aniline (52.6 mg, 0.275 mmol) is pre-mixed, and heats 1 hour in phial, at 90 ℃.After cooling, by the saturated NaHCO of resistates 3/ brine treatment, and extract by ethyl acetate (2x).By the organic layer MgSO of merging 4dry, filter, concentrated, with reversed-phase HPLC, purify (at Zorbax RX-C18 post (250 x 21.2 mm, 7 μ m particle diameters) on, carry out), use 15% to 100% methyl alcohol: 0.1% trifluoroacetic acid aqueous solution gradient elution 48 minutes, flow velocity 15 mL/ minute, provide the trifluoroacetate of title compound. 1H NMR(400 MHz, CD 3OD) δ ppm 2.97(s, 3 H), 3.08(t, J=11.60 Hz, 2 H), 3.22-3.34(m, 2 H), 3.61(d, J=11.90 Hz, 2 H), 3.84(d, J=12.51 Hz, 2 H), 6.95-7.17(m, 3 H), 7.47-7.64(m, 3 H), 7.64-7.88(m, 4 H), 9.06(s, 1 H)。MS(ESI +)m/z 487.3(M+H) +。
Embodiment 2
2-anilino-6-(2-chloro-phenyl-) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
In the phial of adding a cover, the mixture of embodiment 1E (70.0 mg, 0.195 mmol) and aniline (39.1 μ l, 0.428 mmol) is heated 1 hour at 90 ℃.After cooling, by the saturated NaHCO of resistates 3/ brine treatment, and extract by ethyl acetate (2x).By the organic layer MgSO of merging 4dry, filter, concentrated, purifying on 12 g posts, is used ISCO Companion flash chromatographic system, uses CH 2cl 2/ ethyl acetate (8:2 to 7:3) wash-out, provides title compound. 1H NMR(400 MHz, DMSO-d 6) δ ppm 7.08(d, J=1.83 Hz, 1 H), 7.14(t, J=7.48 Hz, 1 H), 7.42(t, J=7.63 Hz, 2 H), 7.54-7.59(m, 2 H), 7.61-7.66(m, 1 H), 7.70-7.74(m, 1 H), 7.79-7.90(m, 3 H), 9.14(s, 1 H), 10.78(s, 1 H)。MS(ESI +)m/z 389.2(M+H) +。
Embodiment 3
6-(2-chloro-phenyl-)-2-(pyridin-4-yl is amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
In the phial of adding a cover, the mixture of embodiment 1E (60.0 mg, 0.167 mmol) and pyridine-4-amine (34.5 mg, 0.367 mmol) is heated 3 hours at 100 ℃.With the HPLC describing in embodiment 1F, purify crude product compound, the trifluoroacetate of title compound is provided. 1H NMR(400 MHz, DMSO-d 6) δ ppm 7.18(d, J=1.83 Hz, 1 H), 7.50-7.68(m, 3 H), 7.69-7.80(m, 1 H), 8.13(d, J=1.83 Hz, 1 H), 8.40(d, J=7.32 Hz, 2 H), 8.75(d, J=7.32 Hz, 2 H), 9.41(s, 1 H), 12.11(s, 1 H)。MS(APCI +)m/z 390.2(M+H) +。
Embodiment 4
6-(2-chloro-phenyl-)-2-[(2'-methyl-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Preparation Example 4 as described in embodiment 1F, with 2'-methyl-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9] alternative 4-(4-methylpiperazine-1-yl) aniline of-7'-amine (WO 2009/151997). 1H NMR(400 MHz, CD 3OD) δ ppm 0.97-1.60(m, 4 H), 3.09(s, 3 H), 3.26(d, J=13.12 Hz, 1 H), 3.66(d, J=12.21 Hz, 1 H), 4.46-4.59(m, 1 H), 4.72(d, J=14.65 Hz, 1 H), 6.96(d, J=8.24 Hz, 1 H), 7.06(d, J=1.83 Hz, 1 H), 7.52-7.61(m, 3 H), 7.66-7.71(m, 2 H), 7.76(s, 1 H), 7.87(d, J=1.83 Hz, 1 H), 9.16(s, 1 H)。MS(ESI +)m/z 484.2(M+H) +。
Embodiment 5
6-(2-chloro-phenyl-)-2-(5,6,7,8-naphthane-2-base is amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Preparation Example 5 as described in embodiment 1F, substitutes 4-(4-methylpiperazine-1-yl) aniline with 5,6,7,8-naphthane-2-amine. 1H NMR(400 MHz, DMSO-d 6) δ ppm 1.63-1.90(m, 4 H), 2.63-2.89(m, 4 H), 7.05-7.12(m, 2 H), 7.51-7.59(m, 4 H), 7.61-7.65(m, 1 H), 7.69-7.75(m, 2 H), 9.10(s, 1 H), 10.64(s, 1 H)。MS(ESI +)m/z 443.3(M+H) +。
Embodiment 6
6-(2-chloro-phenyl-)-2-{[3-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
In adding a cover phial, the mixture of embodiment 1E (60.0 mg, 0.167 mmol) and 3-(4-methylpiperazine-1-yl) aniline (65.4 mg, 0.342 mmol) is heated 40 minutes at 90 ℃.With the HPLC describing in embodiment 1F, purify crude product compound, the trifluoroacetate of title compound is provided. 1H NMR(400 MHz, CD 3OD) δ ppm 2.98(s, 3 H), 3.11(t, J=12.51 Hz, 2 H), 3.25-3.34(m, 2 H), 3.63(d, J=11.60 Hz, 2 H), 3.89(d, J=13.12 Hz, 2 H), 6.85(d, J=7.02 Hz, 1 H), 7.06(d, J=2.14 Hz, 1 H), 7.26-7.48(m, 3 H), 7.53-7.61(m, 3 H), 7.65-7.72(m, 1 H), 7.82(s, 1 H), 9.14(s, 1 H)。MS(ESI +)m/z 487.3(M+H) +。
Embodiment 7
6-(2-chloro-phenyl-)-2-[(4-cyclohexyl phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Preparation Example 7 as described in Example 2, with 4-cyclohexyl aniline, substitute aniline. 1H NMR(400 MHz, CDCl 3) δ ppm 1.35-1.50(m, 4 H), 1.70-1.81(m, 2 H), 1.83-1.95(m, 4 H), 2.46-2.60(m, 1 H), 7.08(d, J=1.53 Hz, 1 H), 7.28(d, J=8.54 Hz, 2 H), 7.46-7.51(m, 3 H), 7.56-7.66(m, 3 H), 7.71(d, J=1.53 Hz, 1 H), 7.93(s, 1 H), 9.24(s, 1 H)。MS(ESI +)m/z 471.3(M+H) +。
Embodiment 8
6-(2-chloro-phenyl-)-2-{[4-(piperidin-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Preparation Example 8 as described in embodiment 1F, substitutes 4-(4-methylpiperazine-1-yl) aniline with 4-(piperidin-1-yl) aniline. 1H NMR(400 MHz, DMSO-d 6) δ ppm 1.55-1.74(m, 2 H), 1.79-1.98(m, 4 H), 3.33-3.57(m, 4 H), 7.10(d, J=1.83 Hz, 1 H), 7.53-7.61(m, 4 H), 7.62-7.66(m, 1 H), 7.72(dd, J=7.48, 1.98 Hz, 1 H), 7.85(s, 1 H), 7.94(d, J=7.63 Hz, 2 H), 9.16(s, 1 H), 10.91(s, 1 H)。MS(ESI +)m/z 472.3(M+H) +。
Embodiment 9
6-(2-chloro-phenyl-)-2-{[4-(pyrrolidin-1-yl methyl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Preparation Example 9 as described in embodiment 1F, substitutes 4-(4-methylpiperazine-1-yl) aniline with 4-(pyrrolidin-1-yl methyl) aniline. 1H NMR(400 MHz, CD 3OD) δ ppm 1.92-2.09(m, 2 H), 2.12-2.36(m, 2 H), 3.07-3.28(m, 2 H), 3.41-3.64(m, 2 H), 4.38(s, 2 H), 7.07(d, J=1.83 Hz, 1 H), 7.47-7.62(m, 5 H), 7.66-7.72(m, 1 H), 7.88(d, J=1.83 Hz, 1 H), 7.96(d, J=8.54 Hz, 2 H), 9.19(s, 1 H)。MS(ESI +)m/z 472.0(M+H) +。
Embodiment 10
6-(2-chloro-phenyl-)-2-{[4-(morpholine-4-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Preparation Example 10 as described in embodiment 1F, substitutes 4-(4-methylpiperazine-1-yl) aniline with 4-morpholino aniline. 1H NMR(400 MHz, DMSO-d 6) δ ppm 3.09-3.20(m, 4 H), 3.75-3.82(m, 4 H), 7.00-7.12(m, 3 H), 7.53-7.66(m, 4 H), 7.70-7.83(m, 3 H), 9.08(s, 1 H), 10.66(s, 1 H)。MS(ESI +)m/z 474.3(M+H) +。
Embodiment 11
6-(2-chloro-phenyl-)-2-{[3-(pyrrolidin-1-yl methyl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
In adding a cover phial, the mixture of embodiment 1E (50.0 mg, 0.139 mmol) and 3-(pyrrolidin-1-yl methyl) aniline (49.0 mg, 0.278 mmol) is heated 1 hour at 110 ℃.With the HPLC describing in embodiment 1F, purify crude product, the trifluoroacetate of title compound is provided. 1H NMR(400 MHz, CD 3OD) δ ppm 1.96-2.10(m, 2 H), 2.14-2.31(m, 2 H), 3.18-3.28(m, 2 H), 3.49-3.65(m, 2 H), 4.44(s, 2 H), 7.07(d, J=1.83 Hz, 1 H), 7.31(d, J=7.32 Hz, 1 H), 7.50-7.63(m, 4 H), 7.66-7.73(m, 1 H), 7.83-8.08(m, 3 H), 8.01(s, 1 H), 9.21(s, 1 H)。MS(ESI +)m/z 472.2(M+H) +。
Embodiment 12
2-[(1-ethanoyl-2,3-dihydro-1H-indoles-6-yl) amino]-6-(2-chloro-phenyl-) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
In Biotage microwave reactor, by embodiment 1E (50.0 mg, 0.139 mmol), 1-(the amino indoline-1-yl of 6-) ethyl ketone (36.7 mg, 0.208 mmol) and the mixture of tosic acid monohydrate (13 mg, 0.069 mmol) in acetonitrile (2 mL) at 160 ℃, heat 30 minutes.Concentrated this reaction mixture, purifies with the described HPLC of embodiment 1F, and the trifluoroacetate of title compound is provided. 1H NMR(400 MHz, DMSO-d 6) δ ppm 2.22(s, 3 H), 3.13(t, J=8.39 Hz, 2 H), 4.15(t, J=8.39 Hz, 2 H), 7.10(d, J=6.41 Hz, 1 H), 7.14-7.25(m, 2 H), 7.51-7.60(m, 2 H), 7.61-7.66(m, 1 H), 7.72(dd, J=7.17, 1.98 Hz, 1 H), 8.39(s, 1 H), 9.11(s, 1 H), 9.41(s, 1 H), 10.82(s, 1 H)。MS(ESI +)m/z 472.3(M+H) +。
Embodiment 13
2-{[4-(4-ethanoyl piperazine-1-yl) phenyl] amino }-6-(2-chloro-phenyl-) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Preparation Example 13 as described in embodiment 1F, substitutes 4-(4-methylpiperazine-1-yl) aniline with 1-(4-(4-aminophenyl) piperazine-1-yl) ethyl ketone. 1H NMR(400 MHz, DMSO-d 6) δ ppm 2.06(s, 3 H), 3.15(d, J=27.16 Hz, 4 H), 3.61(s, brd, 4 H), 7.01-7.14(m, 3 H), 7.50-7.66(m, 4 H), 7.69-7.84(m, 3 H), 9.08(s, 1 H), 10.67(s, 1 H)。MS(ESI +)m/z 515.3(M+H) +。
Embodiment 14
6-(2-aminomethyl phenyl)-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 14A
7-(methylthio group)-3-o-tolyl Kui Linpyrimido quinoline [4,5-d] pyrimidine-2,4 (1H, 3H)-diketone
Preparation Example 14A as described in embodiment 1A (0.15 g), substitutes the chloro-2-isocyanato of 1-benzene with 1-isocyanato-2-toluene.MS(ESI +)m/z 301.1(M+H) +。
Embodiment 14B
The chloro-7-of 2-(methylthio group)-3-o-tolyl Kui Linpyrimido quinoline [4,5-d] pyrimidine-4 (3H)-one
Preparation Example 14B as described in embodiment 1B (0.25 g), with embodiment 14A alternate embodiment 1A.MS(ESI +)m/z 319.0(M+H) +。
Embodiment 14C
2-(2,2-dimethoxy-ethyl is amino)-7-(methylthio group)-3-o-tolyl Kui Linpyrimido quinoline [4,5-d] pyrimidine-4 (3H)-one
Preparation Example 14C as described in embodiment 1C (0.3 g), with embodiment 14B alternate embodiment 1B.MS(ESI +)m/z 388.4(M+H) +。
Embodiment 14D
8-methyl sulfenyl-4-o-tolyl-4H-3,4,7,9,9b-pentaaza-cyclopenta [a] naphthalene-5-ketone
Preparation Example 14D (0.15g) as described in embodiment 1D, with embodiment 14C alternate embodiment 1C.MS(ESI +)m/z 323.9(M+H) +。
Embodiment 14E
8-methanesulfinyl-4-(2-aminomethyl phenyl)-4H-3,4,7,9,9b-pentaaza-cyclopenta [a] naphthalene-5-ketone
Preparation Example 14E (0.1g) as described in embodiment 1E, with embodiment 14D alternate embodiment 1D.MS(ESI +)m/z 340.0(M+H) +。
Embodiment 14F
6-(2-aminomethyl phenyl)-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Preparation Example 14G (0.1g) as described in embodiment 1F, with embodiment 14E alternate embodiment 1E. 1H NMR(300 MHz, DMSO-d 6) δ ppm 1.98-2.13(m, 3 H)2.79-3.05(m, 5 H)3.06-3.33(m, 2 H)3.83(d, J=12.69 Hz, 2 H)6.87-7.25(m, 3 H)7.21-7.53(m, 5 H)7.56-7.89(m, 3 H)8.87-9.23(m, 1 H)9.62(s, 1 H)10.61(s, 1 H)。
MS(ESI +)m/z 340.0(M+H) +。
Embodiment 15
2-{[4-(4-methylpiperazine-1-yl) phenyl] amino }-6-[2-(trifluoromethyl) phenyl] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 15A
7-(methylthio group)-3-(2-(trifluoromethyl) phenyl) Kui Linpyrimido quinoline [4,5-d] pyrimidine-2,4 (1H, 3H)-diketone
Preparation Example 15A as described in embodiment 1A (0.2 g), substitutes the chloro-2-isocyanato of 1-benzene with 1-isocyanato-2-(trifluoromethyl) benzene.MS(ESI +)m/z 355.1(M+H) +。
Embodiment 15B
The chloro-7-of 2-(methylthio group)-3-(2-(trifluoromethyl) phenyl) Kui Linpyrimido quinoline [4,5-d] pyrimidine-4 (3H)-one
Preparation Example 15B as described in embodiment 1B (0.2 g), with embodiment 15A alternate embodiment 1A.MS(ESI +)m/z 372.56(M+H) +。
Embodiment 15C
2-(2,2-dimethoxy-ethyl is amino)-7-(methylthio group)-3-(2-(trifluoromethyl) phenyl) Kui Linpyrimido quinoline [4,5-d] pyrimidine-4 (3H)-one
Preparation Example 15C as described in embodiment 1C (0.28 g), with embodiment 15B alternate embodiment 1B.MS(ESI +)m/z 442.4(M+H) +。
Embodiment 15D
8-methyl sulfenyl-4-(2-trifluoromethyl-phenyl)-4H-3,4,7,9,9b-pentaaza-cyclopenta [a] naphthalene-5-ketone
Preparation Example 15D as described in embodiment 1D (0.1 g), with embodiment 15C alternate embodiment 1C.MS(ESI +)m/z 378.2(M+H) +。
Embodiment 15E
8-methanesulfinyl-4-(2-trifluoromethyl-phenyl)-4H-3,4,7,9,9b-pentaaza-cyclopenta [a] naphthalene-5-ketone
Preparation Example 15E as described in embodiment 1E (0.05 g), with embodiment 15D alternate embodiment 1D.MS(ESI +)m/z 393.99(M+H) +。
Embodiment 15F
2-{[4-(4-methylpiperazine-1-yl) phenyl] amino }-6-[2-(trifluoromethyl) phenyl] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Preparation Example 15F as described in embodiment 1F (0.02 g), with embodiment 15E alternate embodiment 1E. 1H NMR(300 MHz, DMSO-d 6) δ ppm 3.17(s, 2 H)3.52(s, 2 H)3.83(d, J=11.87 Hz, 2 H)6.97-7.16(m, 3 H)7.49-7.84(m, 6 H)7.85-8.02(m, 2 H)9.08(s, 1 H)9.60(s, 1 H)10.68(s, 5 H)。MS(ESI +)m/z 521.2(M+H) +。
Embodiment 16
6-(2-p-methoxy-phenyl)-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 16A
3-(2-p-methoxy-phenyl)-7-(methylthio group) Kui Linpyrimido quinoline [4,5-d] pyrimidine-2,4 (1H, 3H)-diketone
Preparation Example 16A as described in embodiment 1A (0.22 g), substitutes the chloro-2-isocyanato of 1-benzene with 1-isocyanato-2-anisole.MS(ESI +)m/z 317.1(M+H) +。
Embodiment 16B
The chloro-3-of 2-(2-p-methoxy-phenyl)-7-(methylthio group) Kui Linpyrimido quinoline [4,5-d] pyrimidine-4 (3H)-one
Preparation Example 16B as described in embodiment 1B (0.23 g), with embodiment 16A alternate embodiment 1A.MS(ESI +)m/z 334.55(M+H) +。
Embodiment 16C
2-(2,2-dimethoxy-ethyl is amino)-3-(2-p-methoxy-phenyl)-7-(methylthio group) Kui Linpyrimido quinoline [4,5-d] pyrimidine-4 (3H)-one
Preparation Example 16C as described in embodiment 1C (0.28 g), with embodiment 16B alternate embodiment 1B.MS(ESI +)m/z 404.3(M+H) +。
Embodiment 16D
4-(2-methoxyl group-phenyl)-8-methyl sulfenyl-4H-3,4,7,9,9b-pentaaza-cyclopenta [a] naphthalene-5-ketone
Preparation Example 16D as described in embodiment 1D (0.1 g), with embodiment 16C alternate embodiment 1C.MS(ESI +)m/z 341.2(M+H) +。
Embodiment 16E
8-methanesulfinyl-4-(2-methoxyl group-phenyl)-4H-3,4,7,9,9b-pentaaza-cyclopenta [a] naphthalene-5-ketone
Preparation Example 16E as described in embodiment 1E (0.05 g), with embodiment 16D alternate embodiment 1D.MS(ESI +)m/z 356.03(M+H) +。
Embodiment 16F
6-(2-p-methoxy-phenyl)-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Preparation Example 16F (0.015g) as described in embodiment 1F, with embodiment 16E alternate embodiment 1E. 1H NMR(300 MHz, DMSO-d 6) δ ppm 2.80-3.04(m, 5 H)3.07-3.29(m, 2 H)3.54(d, J=11.90 Hz, 2 H)3.66-3.77(m, 3 H)3.83(d, J=13.09 Hz, 2 H)6.98-7.15(m, 5 H)7.23(d, J=7.14 Hz, 1 H)7.37(dd, J=7.93, 1.59 Hz, 1 H)7.44-7.54(m, 1 H)7.72(s, 3 H)9.05(s, 1 H)9.59(s, 1 H)10.61(s, 1 H)。MS(ESI +)m/z 483.3(M+H) +。
Embodiment 17
6-(2-chloro-phenyl-)-2-{[2-methoxyl group-4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Preparation Example 17 as described in embodiment 1F, substitutes 4-(4-methylpiperazine-1-yl) aniline with 2-methoxyl group-4-(4-methylpiperazine-1-yl) aniline. 1H NMR(400 MHz, CD 3OD) δ ppm 2.98(s, 3 H), 3.10(t, J=12.51 Hz, 2 H), 3.23-3.35(m, 2 H), 3.63(d, J=11.60 Hz, 2 H), 3.83-3.97(m, 5 H), 6.68(s, 1 H), 6.77(d, J=2.14 Hz, 1 H), 7.04(s, 1 H), 7.48-7.63(m, 3 H), 7.66-7.72(m, 1 H), 7.72-8.15(m, 2 H), 9.07(s, 1 H)。MS(ESI +)m/z 517.3(M+H) +。
Embodiment 18
6-(2-chloro-phenyl-)-2-[(1-methyl isophthalic acid, 2,3,4-tetrahydroquinoline-7-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
In adding a cover phial, by embodiment 1E (60.0 mg, 0.167 mmol) and 1-methyl isophthalic acid, the mixture of 2,3,4-tetrahydroquinoline-7-amine (48.7 mg, 0.300 mmol) heats 1 hour at 90 ℃.After cooling, methyl-sulphoxide/methyl alcohol for resistates (2 mL) is processed.Filtering-depositing, with methyl alcohol and water washing, dry by bake oven, title compound is provided. 1H NMR(400 MHz, DMSO-d 6) δ ppm 1.77-1.99(m, 2 H), 2.69(t, J=6.26 Hz, 2 H), 2.90(s, 3 H), 3.11-3.28(m, 2 H), 6.92(d, J=7.93 Hz, 1 H), 7.02(d, J=7.32 Hz, 1 H), 7.07(s, 1 H), 7.18(s, 1 H), 7.50-7.65(m, 3 H), 7.69-7.74(m, 2 H), 9.09(s, 1 H), 10.53(s, 1 H)。MS(ESI +)m/z 458.2(M+H) +。
Embodiment 19
6-(2-chloro-phenyl-)-2-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
By embodiment 1E (60.0 mg, 0.167 mmol), N, N-diisopropylethylamine (0.058 mL, 0.334 mmol) and 6-amino-2H-benzo [b] [1,4] oxazine-3 (4H)-one (49.3 mg, 0.300 mmol) mixture in DMF (1.5 mL) at room temperature stirs 2 hours.By the saturated NaHCO of reaction mixture 3/ brine treatment, and extract by ethyl acetate (2x).By the organic layer MgSO of merging 4dry, filter, concentrated, with the described HPLC of embodiment 1F, purify, the trifluoroacetate of title compound is provided. 1H NMR(500 MHz, DMSO-d 6) δ ppm 4.57(s, 2 H), 6.99(d, J=7.93 Hz, 1 H), 7.08-7.13(m, 1 H), 7.16-7.21(m, 1 H), 7.53-7.60(m, 2 H), 7.62-7.65(m, 1 H), 7.70-7.74(m, 1 H), 7.87(s, 1 H), 8.16(s, 1 H), 9.11(s, 1 H), 10.79(s, 1 H)。MS(ESI +)m/z 460.2(M+H) +。
Embodiment 20
7-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino }-3,4-dihydro-isoquinoline-2 (1H)-formic acid tertiary butyl ester
In the phial of adding a cover, by embodiment 1E (0.900 g, 2.501 mmol) and 7-amino-3, the mixture of 4-dihydro-isoquinoline-2 (1H)-formic acid tertiary butyl ester (0.994 g, 4.00 mmol) heats 1 hour at 90 ℃.This reaction mixture is suspended in ethyl acetate, and stir.Cross filter solid, by ethyl acetate, wash.By filter cake at saturated NaHCO 3in the aqueous solution, stir, filter, wash with water, dry by bake oven, title compound is provided.By ethyl acetate, dilute filtrate, and use saturated NaHCO 3washing.By organic layer MgSO 4dry, filter, concentrated, purifying on 80 g posts, is used ISCO Companion flash chromatographic system, uses CH 2cl 2/ ethyl acetate (6:4 to 5:5) wash-out, provides title compound. 1H NMR(300 MHz, DMSO-d 6) δ ppm 1.44(s, 9 H), 2.77(t, J=5.75 Hz, 2 H), 3.58(t, J=5.75 Hz, 2 H), 4.54(s, 2 H), 7.07(d, J=1.59 Hz, 1 H), 7.21(d, J=8.72 Hz, 1 H), 7.53-7.66(m, 5 H), 7.69-7.74(m, 1 H), 7.76(d, J=1.59 Hz, 1 H), 9.12(s, 1 H), 10.71(s, 1 H)。MS(ESI +)m/z 544.1(M+H) +。
Embodiment 21
6-(2-chloro-phenyl-)-2-(1,2,3,4-tetrahydroisoquinoline-7-base is amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
By embodiment 20 (0.357 g, 0.656 mmol) and trifluoroacetic acid (0.506 mL, 6.56 mmol) at CH 2cl 2mixture in (6 mL) at room temperature stirs 6 hours.Concentrated this reaction mixture, purifies with the described HPLC of embodiment 1F, and the trifluoroacetate of title compound is provided. 1H NMR(300 MHz, CD 3OD) δ ppm 3.14(t, J=6.35 Hz, 2 H), 3.54(t, J=6.35 Hz, 2 H), 4.43(s, 2 H), 7.07(d, J=1.98 Hz, 1 H), 7.31(d, J=8.33 Hz, 1 H), 7.52-7.63(m, 3 H), 7.66-7.72(m, 2 H), 7.76(s, 1 H), 7.87(d, J=1.98 Hz, 1 H), 9.18(s, 1 H)。MS(ESI +)m/z 444.2(M+H) +。
Embodiment 22
6-(2-chloro-phenyl-)-2-{[3-methyl-4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
In the phial of adding a cover, the mixture of embodiment 1E (60.0 mg, 0.167 mmol) and 3-methyl-4-(4-methylpiperazine-1-yl) aniline (54.8 mg, 0.267 mmol) is heated 1 hour at 95 ℃.As embodiment 1F description, with HPLC, purify crude product, the trifluoroacetate of title compound is provided. 1H NMR(400 MHz, DMSO-d 6) δ ppm 2.31(s, 3 H), 2.90(s, 3 H), 2.96(t, J=12.05 Hz, 2 H), 3.22(d, J=11.29 Hz, 2 H), 3.53(d, J=11.29 Hz, 2 H), 7.08(d, J=1.53 Hz, 1 H), 7.15(d, J=7.63 Hz, 1 H), 7.53-7.65(m, 4 H), 7.72(dd, J=7.48, 1.98 Hz, 1 H), 7.77(s, 1 H), 9.11(s, 1 H), 9.78(s, 1 H), 10.71(s, 1 H)。MS(ESI +)m/z 501.2(M+H) +。
Embodiment 23
6-allyl group-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 23A
3-allyl group-7-(methylthio group) Kui Linpyrimido quinoline [4,5-d] pyrimidine-2,4 (1H, 3H)-diketone
Preparation Example 23A as described in embodiment 1A (0.25 g), substitutes the chloro-2-isocyanato of 1-benzene with allyl isocyanate.MS(ESI +)m/z 250.5(M+H) +。
Embodiment 23B
The chloro-7-of 3-allyl group-2-(methylthio group) Kui Linpyrimido quinoline [4,5-d] pyrimidine-4 (3H)-one
Preparation Example 23B as described in embodiment 1B (0.3 g), with embodiment 23A alternate embodiment 1A.MS(ESI +)m/z 269.2(M+H) +。
Embodiment 23C
3-allyl group-2-(2,2-dimethoxy-ethyl is amino)-7-(methylthio group) Kui Linpyrimido quinoline [4,5-d] pyrimidine-4 (3H)-one
Preparation Example 23C as described in embodiment 1C (0.28 g), with embodiment 23B alternate embodiment 1B.MS(ESI +)m/z 338.3(M+H) +。
Embodiment 23D
4-allyl group-8-methyl sulfenyl-4H-3,4,7,9,9b-pentaaza-cyclopenta [a] naphthalene-5-ketone
Preparation Example 23D as described in embodiment 1D (0.05 g), with embodiment 23C alternate embodiment 1C.MS(ESI +)m/z 341.2(M+H) +。
Embodiment 23E
4-allyl group-8-methanesulfinyl-4H-3,4,7,9,9b-pentaaza-cyclopenta [a] naphthalene-5-ketone
Preparation Example 23E as described in embodiment 1E (0.04 g), with embodiment 23D alternate embodiment 1D.MS(ESI +)m/z 289.9(M+H) +。
Embodiment 23F
6-allyl group-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Preparation Example 23F as described in embodiment 1F (0.02 g), with embodiment 23E alternate embodiment 1E. 1H NMR(300 MHz, DMSO-d 6) δ ppm 2.92(d, 5 H)3.18(d, J=10.51 Hz, 2 H)3.64-3.96(m, 2 H)4.51-4.88(m, 2 H)4.99-5.37(m, 2 H)5.75-6.16(m, 1 H)6.95-7.13(m, 3 H)7.18(d, J=1.70 Hz, 1 H)7.52-7.90(m, 3 H)8.87-9.17(m, 1 H)9.59(s, 1 H)10.52(s, 1 H)。MS(ESI +)m/z 417.2(M+H) +。
Embodiment 24
6-cyclohexyl-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 24A
3-cyclohexyl-7-(methylthio group) Kui Linpyrimido quinoline [4,5-d] pyrimidine-2,4 (1H, 3H)-diketone
Preparation Example 24A as described in embodiment 1A (0.22 g), substitutes the chloro-2-isocyanato of 1-benzene with cyclic isocyanate polyhexamethylene.MS(ESI +)m/z 292.48(M+H) +。
Embodiment 24B
The chloro-3-cyclohexyl-7-of 2-(methylthio group) Kui Linpyrimido quinoline [4,5-d] pyrimidine-4 (3H)-one
Preparation Example 24B as described in embodiment 1B (0.21 g), with embodiment 24A alternate embodiment 1A.MS(ESI +)m/z 310.92(M+H) +。
Embodiment 24C
3-cyclohexyl-2-(2,2-dimethoxy-ethyl is amino)-7-(methylthio group) Kui Linpyrimido quinoline [4,5-d] pyrimidine-4 (3H)-one
Preparation Example 24C as described in embodiment 1C (0.25 g), with embodiment 24B alternate embodiment 1B.MS(ESI +)m/z 380.4(M+H) +。
Embodiment 24D
4-cyclohexyl-8-methyl sulfenyl-4H-3,4,7,9,9b-pentaaza-cyclopenta [a] naphthalene-5-ketone
Preparation Example 24D as described in embodiment 1D (0.137 g), with embodiment 24C alternate embodiment 1C.MS(ESI +)m/z 315.1(M+H) +。
Embodiment 24E
4-cyclohexyl-8-methanesulfinyl-4H-3,4,7,9,9b-pentaaza-cyclopenta [a] naphthalene-5-ketone
Preparation Example 24E as described in embodiment 1E (0.14 g), with embodiment 24D alternate embodiment 1D.MS(ESI +)m/z 332.3(M+H) +。
Embodiment 24F
6-cyclohexyl-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Preparation Example 24F as described in embodiment 1F (0.055 g), with embodiment 24E alternate embodiment 1E. 1H NMR(300 MHz, DMSO-d 6) δ ppm 1.07-1.52(m, 4 H)1.66(s, 4 H)1.83(s, 2 H)2.54-2.71(m, 2 H)2.79-3.04(m, 5 H)3.05-3.32(m, 2 H)3.81(d, J=13.09 Hz, 2 H)4.80-5.07(m, 1 H)6.89-7.14(m, 3 H)7.19(d, J=1.98 Hz, 1 H)7.51-7.84(m, 3 H)8.87-9.14(m, 1 H)9.62(s, 1 H)10.48(s, 1 H)。MS(ESI +)m/z 459.03(M+H) +。
Embodiment 25
6-(2-chloro-phenyl-)-9-methyl-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 25A
3-(2-chloro-phenyl-)-7-(methylthio group)-2-(2-oxopropyl is amino) Kui Linpyrimido quinoline [4,5-d] pyrimidine-4 (3H)-one
By 1-aminopropan-2-ketone (0.031 g, 0.425 mmol) and embodiment 1B (0.120 g, 0.354 mmol), the mixture in acetonitrile (7 mL) heats 40 minutes at 80 ℃.Concentrated this mixture, uses saturated NaHCO 3the aqueous solution is processed, and extracts by ethyl acetate (2x).Use MgSO 4the dry organic layer merging, filters, concentrated, and title compound is provided.
Embodiment 25B
4-(the chloro-phenyl of 2-)-1-methyl-8-methyl sulfenyl-4H-3,4,7,9,9b-pentaaza-cyclopenta [a] naphthalene-5-ketone
Embodiment 25A (0.115 g) is processed with dense HCl (0.03 mL) in acetonitrile (1.5 mL), and by this mixture in Biotage MW, at 160 ℃, heat 40 minutes.Evaporating solvent.By the saturated NaHCO of resistates 3the aqueous solution is processed, and extracts by ethyl acetate (2x).By the organic layer MgSO of merging 4dry, filter, concentrated, purifying on 12 g posts, is used ISCO Companion flash chromatographic system, uses CH 2cl 2/ eluent ethyl acetate, provides title compound.
Embodiment 25C
4-(the chloro-phenyl of 2-)-8-methanesulfinyl-1-methyl-4H-3,4,7,9,9b-pentaaza-cyclopenta [a] naphthalene-5-ketone
By metachloroperbenzoic acid (0.021 g, 0.092 mmol) and embodiment 25B (0.030 g, 0.084 mmol), the mixture in methylene dichloride (4 mL) stirs 2 hours.With methylene dichloride, dilute this reaction soln, use saturated NaHCO 3and Na 2s 2o 3solution washing.Use MgSO 4dry organic layer, concentrated, title compound is provided.
Embodiment 25D
6-(2-chloro-phenyl-)-9-methyl-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
In phial, the mixture of embodiment 25C (24.5 mg, 0.066 mmol) and 4-(4-methylpiperazine-1-yl) aniline (27.6 mg, 0.144 mmol) is heated 1 hour at 90 ℃.As embodiment 1F description, with HPLC, purify crude product, the trifluoroacetate of title compound is provided. 1H NMR(400 MHz, CD 3OD) δ ppm 2.65(s, 3 H), 2.98(s, 3 H), 3.06(t, J=12.82 Hz, 2 H), 3.24-3.33(m, 2 H), 3.62(d, J=11.90 Hz, 2 H), 3.85(d, J=12.82 Hz, 2 H), 6.72(s, 1 H), 7.07(d, J=8.54 Hz, 2 H), 7.49-7.62(m, 5 H), 7.63-7.72(m, 1 H), 9.11(s, 1 H)。MS(ESI +)m/z 501.3(M+H) +。
Embodiment 26
6-(2-chloro-phenyl-)-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } Kui Linpyrimido quinoline [5,4-e] [1,2,4] triazolos [4,3-a] pyrimidine-5 (6H)-one
Embodiment 26A
4-(the chloro-phenyl of 2-)-8-methyl sulfenyl-4H-2,3,4,7,9,9b-, six azepines-cyclopenta [a] naphthalene-5-ketone
In Biotage microwave reactor, by embodiment 1B (0.150 g, 0.442 mmol) and formyl hydrazine (0.066 g, 1.11 mmol), the mixture in acetonitrile (7 mL) heats 15 minutes at 150 ℃.Cross filter solid.Concentrated filtrate, uses saturated NaHCO 3the aqueous solution is processed, and extracts by ethyl acetate (2x).By the organic layer MgSO of merging 4dry, filter, concentrated, purifying on 12 g posts, is used ISCO Companion flash chromatographic system, uses CH 2cl 2/ ethyl acetate (3:7 to 2:8) wash-out, provides title compound.
Embodiment 26B
4-(the chloro-phenyl of 2-)-8-methanesulfinyl-4H-2,3,4,7,9,9b-, six azepines-cyclopenta [a] naphthalene-5-ketone
As described in embodiment 1E, prepare title compound, with embodiment 26A alternate embodiment 1D.
Embodiment 26C
6-(2-chloro-phenyl-)-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } Kui Linpyrimido quinoline [5,4-e] [1,2,4] triazolos [4,3-a] pyrimidine-5 (6H)-one
In phial, the mixture of embodiment 26B (10.0 mg, 0.028 mmol) and 4-(4-methylpiperazine-1-yl) aniline (11.7 mg, 0.061 mmol) is heated 1 hour at 90 ℃.As embodiment 1F description, with HPLC, purify crude product, the trifluoroacetate of title compound is provided. 1H NMR(400 MHz, CD 3OD) δ ppm 2.99(s, 3 H), 3.03-3.16(m, 2 H), 3.24-3.38(m, 2 H), 3.50-3.71(m, 2 H), 3.78-3.98(m, 2 H), 7.02-7.19(m, 2 H), 7.50-7.63(m, 3 H), 7.63-7.81(m, 3 H), 9.10-9.22(m, 2 H)。MS(ESI +)m/z 488.3(M+H) +。
Embodiment 27
6-(2-chloro-phenyl-)-9-methyl-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } Kui Linpyrimido quinoline [5,4-e] [1,2,4] triazolos [4,3-a] pyrimidine-5 (6H)-one
Embodiment 27A
4-(the chloro-phenyl of 2-)-1-methyl-8-methyl sulfenyl-4H-2,3,4,7,9,9b-, six azepines-cyclopenta [a] naphthalene-5-ketone
In Biotage microwave reactor, by embodiment 1B (0.150 g, 0.442 mmol) and acethydrazide (0.072 g, 0.973 mmol), the mixture in acetonitrile (5 mL) heats 15 minutes at 150 ℃.Cross filter solid.Concentrated filtrate, uses saturated NaHCO 3the aqueous solution is processed, and extracts by ethyl acetate (2x).By the organic layer MgSO of merging 4dry, filter, concentrated, purifying on 12 g posts, is used ISCO Companion flash chromatographic system, uses CH 2cl 2/ ethyl acetate (3:7 to 2:8) wash-out, provides title compound.
Embodiment 27B
4-(the chloro-phenyl of 2-)-8-methanesulfinyl-1-methyl-4H-2,3,4,7,9,9b-, six azepines-cyclopenta [a] naphthalene-5-ketone
As described in embodiment 1E, prepare title compound, with embodiment 27A alternate embodiment 1D.
Embodiment 27C
6-(2-chloro-phenyl-)-9-methyl-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } Kui Linpyrimido quinoline [5,4-e] [1,2,4] triazolos [4,3-a] pyrimidine-5 (6H)-one
In phial, the mixture of embodiment 27B (44.7 mg, 0.119 mmol) and 4-(4-methylpiperazine-1-yl) aniline (50.2 mg, 0.262 mmol) is heated 1 hour at 90 ℃.As embodiment 1F description, with HPLC, purify crude product, the trifluoroacetate of title compound is provided.1H NMR(400 MHz, CD 3OD) δ ppm 2.80(s, 2 H), 2.98(s, 4 H), 3.06(t, J=12.66 Hz, 2 H), 3.25-3.34(m, 2 H), 3.62(d, J=10.68 Hz, 2 H), 3.86(d, J=11.90 Hz, 2 H), 6.91-7.16(m, 2 H), 7.46-7.65(m, 5 H), 7.66-7.73(m, 1 H), 9.12(s, 1 H)。MS(APCI +)m/z 502.2(M+H) +。
Embodiment 28
4-(2-chloro-phenyl-)-8-{[4-(4-methylpiperazine-1-yl) phenyl] amino } Kui Linpyrimido quinoline [5,4-e] tetrazolo [1,5-a] pyrimidine-5 (4H)-one
Embodiment 28A
4-(the chloro-phenyl of 2-)-8-methyl sulfenyl-4H-1,2,3,4,7,9,9b-, seven azepines-cyclopenta [a] naphthalene-5-ketone
By embodiment 1B (0.175 g, 0.516 mmol) and sodiumazide (0.037 g, 0.568 mmol), the mixture in DMF (5 mL) heats 1 hour at 70 ℃.Water and salt solution dilute this reaction mixture, by ethyl acetate (2X), extract.By salt solution for organic layer (2x) washing merging, use MgSO 4dry, filter, concentrated, purifying on 12 g posts, is used ISCO Companion flash chromatographic system, uses CH 2cl 2/ ethyl acetate (95:5 to 90:10) wash-out, provides title compound.
Embodiment 28B
4-(the chloro-phenyl of 2-)-8-methanesulfinyl-4H-1,2,3,4,7,9,9b-, seven azepines-cyclopenta [a] naphthalene-5-ketone
As described in embodiment 1E, prepare title compound, with embodiment 28A alternate embodiment 1D.
Embodiment 28C
4-(2-chloro-phenyl-)-8-{[4-(4-methylpiperazine-1-yl) phenyl] amino } Kui Linpyrimido quinoline [5,4-e] tetrazolo [1,5-a] pyrimidine-5 (4H)-one
In phial, the mixture of embodiment 28B (65.4 mg, 0.181 mmol) and 4-(4-methylpiperazine-1-yl) aniline (76 mg, 0.398 mmol) is heated 1 hour at 90 ℃.After cooling, by the saturated NaHCO of resistates 3the aqueous solution/brine treatment, and extract by ethyl acetate (2x).By the organic layer MgSO of merging 4dry, filter, concentrated, with the described HPLC of embodiment 1F, purify, the trifluoroacetate of title compound is provided. 1H NMR(300 MHz, DMSO-d 6) δ ppm 2.87(s, 3 H), 2.92-3.05(m, 2 H),3.11-3.24(m, 2 H), 3.54(d, J=12.29 Hz, 2 H), 3.75-3.94(m, 2 H), 6.92-7.23(m, 2 H), 7.51-7.72(m, 4 H), 7.76-7.89(m, 2 H), 9.58(s, 1 H), 10.95-11.10(m, 1 H)。MS(ESI +)m/z 489.0(M+H) +。
Embodiment 29
6-(2-chloro-phenyl-)-2-(4-[4-(third-2-yl) piperazine-1-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 1F, prepare title compound, with 4-(4-sec.-propyl piperazine-1-yl) aniline, substitute 4-(4-methylpiperazine-1-yl) aniline. 1H NMR(400 MHz, CD 3OD)δ 1.43(d, J=6.7 Hz, 6H), 3.07(t, J=12.0 Hz, 2H), 3.38-3.23(m, 2H), 3.63-3.57(m, 3H), 3.89(d, J=12.8 Hz, 2H), 7.10-7.04(m, 3H), 7.61-7.52(m, 3H), 7.76-7.63(m, 3H), 7.80-7.72(m, 1H), 9.10(s, 1H)。MS(ESI +)m/z 515.2(M+H) +。
Embodiment 30
6-(2-chloro-phenyl-)-2-(4-[4-(cyclohexyl methyl) piperazine-1-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 1F, prepare title compound, with 4-(4-(cyclohexyl methyl) piperazine-1-yl) aniline, substitute 4-(4-methylpiperazine-1-yl) aniline. 1H NMR(400 MHz, CD 3OD)δ 1.17-1.01(m, 2H), 1.48-1.19(m, 3H), 2.00-1.67(m, 6H), 3.08(d, J=6.9 Hz, 2H), 3.16(d, J=11.1 Hz, 2H), 3.35-3.22(m, 2H), 3.67(d, J=11.1 Hz, 2H), 3.83(d, J=13.4 Hz, 2H), 7.10-7.05(m, 3H), 7.62-7.53(m, 3H), 7.90-7.63(m, 4H), 9.10(s, 1H)。MS(ESI +)m/z 569.3(M+H) +。
Embodiment 31
3-{[4-(4-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } phenyl) piperazine-1-yl] methyl } benzonitrile
As described in embodiment 1F, prepare title compound, with 3-((4-(4-aminophenyl) piperazine-1-yl) methyl) benzonitrile, substitute 4-(4-methylpiperazine-1-yl) aniline. 1H NMR(400 MHz, CD 3OD)δ 3.58-3.26(m, 8H), 4.49(s, 2H), 7.08-7.02(m, 3H), 7.59-7.52(m, 3H), 7.79-7.65(m, 4H), 7.93-7.85(m, 3H), 7.96(t, J=1.4 Hz, 1H), 9.07(s, 1H)。MS(ESI +)m/z 588.2(M+H) +。
Embodiment 32
The chloro-4-of 2-{[3-(4-methylpiperazine-1-yl) phenyl] amino }-6-(2-chloro-phenyl-) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 1F, prepare title compound, with the chloro-4-of 3-(4-methylpiperazine-1-yl) aniline, substitute 4-(4-methylpiperazine-1-yl) aniline. 1H NMR(400 MHz, CD 3OD)δ 3.00(s, 3H), 3.21-3.07(m, 2H), 3.39-3.33(m, 2H), 3.58-3.49(m, 2H), 3.69-3.59(m, 2H), 7.07(d, J=1.9 Hz, 1H), 7.37-7.21(m, 1H), 7.66-7.53(m, 3H), 7.83-7.64(m, 3H), 8.01(d, J=2.3 Hz, 1H), 9.15(bs, 1H)。MS(ESI +)m/z 521.2(M+H) +。
Embodiment 33
6-(2-chloro-phenyl-)-2-(the fluoro-4-[4-of 3-(third-2-yl) piperazine-1-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 1F, prepare title compound, with the fluoro-4-of 3-(4-sec.-propyl piperazine-1-yl) aniline, substitute 4-(4-methylpiperazine-1-yl) aniline. 1H NMR(400 MHz, CD 3OD)δ 1.43(d, J=6.7 Hz, 6H), 3.15(t, J=11.8 Hz, 2H), 3.44-3.31(m, 2H), 3.71-3.53(m, 5H), 7.07(d, J=1.5 Hz, 1H), 7.14(t, J=8.4 Hz, 1H), 7.61-7.51(m, 4H), 7.71-7.66(m, 1H), 7.75(d, J=14.5 Hz, 1H), 7.83(s, 1H), 9.15(s, 1H)。MS(ESI +)m/z 533.2(M+H) +。
Embodiment 34
6-(2-chloro-phenyl-)-2-[(2-methyl isophthalic acid, 2,3,4-tetrahydroisoquinoline-7-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
By tetrahydrofuran (THF) (4 mL) triethylamine for solution (0.124 mL, 0.893 mmol) and the CH of embodiment 21 (0.120 g, 0.179 mmol) 3i (0.034 mL, 0.536 mmol) processes.Stir this reaction mixture 4 hours.By ethyl acetate, dilute this mixture, and use saturated NaHCO 3with salt water washing.By organic layer MgSO 4dry, filter, concentrated, with reversed-phase HPLC, purify (at Zorbax RX-C18 post (250 x 21.2 mm, 7 μ m particle diameters) on, carry out), use 15% to 100% methyl alcohol: 0.1% trifluoroacetic acid aqueous solution gradient elution 48 minutes, flow velocity 15 mL/ minute, provide the trifluoroacetate of title compound. 1H NMR(400 MHz, CD 3OD)δ 3.09(s, 3H), 3.28-3.20(m, 2H), 3.49-3.41(m, 1H), 3.84-3.75(m, 1H), 4.46-4.38(m, 1H), 4.68-4.60(m, 1H), 7.07(d, J=1.9 Hz, 1H), 7.34(d, J=8.3 Hz, 1H), 7.63-7.48(m, 3H), 7.73-7.66(m, 2H), 7.78(s, 1H), 7.88(d, J=1.8 Hz, 1H), 9.18(s, 1H)。MS(ESI +)m/z 458.1(M+H) +。
Embodiment 35
6-(2-chloro-phenyl-)-2-(4-[2-(dimethylamino) oxyethyl group] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 1F, prepare title compound, with 4-(2-(dimethylamino) oxyethyl group) aniline, substitute 4-(4-methylpiperazine-1-yl) aniline. 1H NMR(400 MHz, CD 3OD)δ 3.00(s, 6H), 3.65-3.58(m, 2H), 4.38(t, J=4.7 Hz, 2H), 7.12-7.03(m, 3H), 7.62-7.52(m, 3H), 7.82-7.65(m, 4H), 9.11(s, 1H)。MS(ESI +)m/z 476.2(M+H) +。
Embodiment 36
6-(2-chloro-phenyl-)-2-(4-[2-(morpholine-4-yl) oxyethyl group] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 1F, prepare title compound, with 4-(2-morpholino oxyethyl group) aniline, substitute 4-(4-methylpiperazine-1-yl) aniline. 1H NMR(400 MHz, CD 3OD)δ 3.38-3.26(m, 2H), 3.70-3.52(m, 4H), 3.91-3.78(m, 2H), 4.14-4.00(m, 2H), 4.45-4.39(m, 2H), 7.10-7.03(m, 3H), 7.62-7.53(m, 3H), 7.90-7.66(m, 4H), 9.10(bs, 1H)。MS(ESI +)m/z 518.2(M+H) +。
Embodiment 37
6-(2-chloro-phenyl-)-2-{[3-methyl-4-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 1F, prepare title compound, with 3-methyl-4-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) aniline, substitute 4-(4-methylpiperazine-1-yl) aniline. 1H NMR(400 MHz, CD 3OD)δ 2.30-2.14(m, 2H), 2.39(s, 3H), 3.01(s, 3H), 3.22-3.17(m, 2H), 3.51-3.25(m, 3H), 3.68-3.54(m, 3H), 7.06(d, J=1.8 Hz, 1H), 7.25-7.17(m, 1H), 7.63-7.50(m, 4H), 7.70-7.67(m, 2H), 7.81(s, 1H), 9.12(s, 1H)。MS(ESI +)m/z 515.2(M+H) +。
Embodiment 38
6-(2-chloro-phenyl-)-2-{[4-(1-methyl piperidine-4-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 1F, prepare title compound, with 4-(1-methyl piperidine-4-yl) aniline, substitute 4-(4-methylpiperazine-1-yl) aniline. 1H NMR(400 MHz, CD 3OD)δ 1.11(d, J=6.5 Hz, 3H), 1.78-1.64(m, 2H), 1.96-1.86(m, 1H), 2.13-2.04(m, 2H), 3.72-3.62(m, 4H), 7.07(d, J=1.9 Hz, 1H), 7.62-7.53(m, 3H), 7.73-7.66(m, 3H), 7.90(d, J=1.9 Hz, 1H), 8.10-8.03(m, 2H), 9.20(s, 1H)。MS(ESI +)m/z 486.0(M+H) +。
Embodiment 39
2-{[4-(4-methylpiperazine-1-yl) phenyl] amino }-6-phenylimidazole [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one also
Embodiment 39A
7-(methylthio group)-3-phenyl pyrimidine is [4,5-d] pyrimidine-2 also, 4 (1H, 3H)-diketone
As described in embodiment 1A, prepare title compound (0.22 g), with isocyanato benzene, substitute the chloro-2-isocyanato of 1-benzene.MS(ESI +)m/z 287.1(M+H) +。
Embodiment 39B
The chloro-7-of 2-(methylthio group)-3-phenyl pyrimidine is [4,5-d] pyrimidine-4 (3H)-one also
As described in embodiment 1B, prepare title compound (0.20 g), with embodiment 39A alternate embodiment 1A.MS(ESI +)m/z 304.8(M+H) +。
Embodiment 39C
2-(2,2-dimethoxy-ethyl is amino)-7-(methylthio group)-3-phenyl pyrimidine is [4,5-d] pyrimidine-4 (3H)-one also
As described in embodiment 1C, prepare title compound (0.23 g), with embodiment 39B alternate embodiment 1B.MS(ESI +)m/z 374.05(M+H) +。
Embodiment 39D
8-methyl sulfenyl-4-phenyl-4H-3,4,7,9,9b-pentaaza-cyclopenta [a] naphthalene-5-ketone
As described in embodiment 1D, prepare title compound (0.17g), with embodiment 39C alternate embodiment 1C.MS(ESI +)m/z 309.9(M+H) +。
Embodiment 39E
8-methanesulfinyl-4-phenyl-4H-3,4,7,9,9b-pentaaza-cyclopenta [a] naphthalene-5-ketone
As described in embodiment 1E, prepare title compound (0.17g), with embodiment 39D alternate embodiment 1D.MS(ESI +)m/z 325.9(M+H) +。
Embodiment 39F
2-{[4-(4-methylpiperazine-1-yl) phenyl] amino }-6-phenylimidazole [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one also
As described in embodiment 1F, prepare title compound (0.075g), with embodiment 39E alternate embodiment 1E.Use preparative HPLC to carry out purifying (on Phenomenex Luna C8 (2) 5 μ m 100 AXIA posts (30mm * 75mm)).Use the gradient of acetonitrile (A) and 0.1% trifluoroacetic acid/water (B), flow velocity 50 mL/min (0-0.5 min, 10% A; 0.5-7.0 min linear gradient, 10-95% A; 7.0-10.0 min, 95% A; 10.0-12.0 min linear gradient, 95-10% A). 1H NMR(300 MHz, DMSO-d 6)δ 2.82-3.04(m, 5 H)3.06-3.30(m, 2 H)3.54(d, J=11.87 Hz, 4 H)7.01-7.14(m, 3 H)7.38-7.62(m, 6 H)7.74(s, 2 H)9.06(s, 1 H)9.65(s, 1 H)10.58(s, 1 H)。MS(ESI +)m/z 453.3(M+H) +。
Embodiment 40
6-(the chloro-4-aminomethyl phenyl of 2-)-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 40A
3-(the chloro-4-aminomethyl phenyl of 2-)-7-(methylthio group) Kui Linpyrimido quinoline [4,5-d] pyrimidine-2,4 (1H, 3H)-diketone
As described in embodiment 1A, prepare title compound (0.54 g), with the chloro-1-isocyanato-4-of 2-toluene, substitute the chloro-2-isocyanato of 1-benzene.MS(ESI +)m/z 335.1(M+H) +。
Embodiment 40B
The chloro-3-of 2-(the chloro-4-aminomethyl phenyl of 2-)-7-(methylthio group) Kui Linpyrimido quinoline [4,5-d] pyrimidine-4 (3H)-one
As described in embodiment 1B, prepare title compound (0.30 g), with embodiment 40A alternate embodiment 1A.MS(ESI +)m/z 353.0(M+H) +。
Embodiment 40C
3-(the chloro-4-aminomethyl phenyl of 2-)-2-(2,2-dimethoxy-ethyl is amino)-7-(methylthio group) Kui Linpyrimido quinoline [4,5-d] pyrimidine-4 (3H)-one
As described in embodiment 1C, prepare title compound (0.35 g), with embodiment 40B alternate embodiment 1B.MS(ESI +)m/z 422.13(M+H) +。
Embodiment 40D
4-(the chloro-4-methyl-phenyl of 2-)-8-methyl sulfenyl-4H-3,4,7,9,9b-pentaaza-cyclopenta [a] naphthalene-5-ketone
As described in embodiment 1D, prepare title compound (0.29g), with embodiment 40C alternate embodiment 1C.MS(ESI +)m/z 358.12(M+H) +。
Embodiment 40E
4-(the chloro-4-methyl-phenyl of 2-)-8-methanesulfinyl-4H-3,4,7,9,9b-pentaaza-cyclopenta [a] naphthalene-5-ketone
As described in embodiment 1E, prepare title compound (0.29g), with embodiment 40D alternate embodiment 1D.MS(ESI +)m/z 373.9(M+H) +。
Embodiment 40F
6-(the chloro-4-aminomethyl phenyl of 2-)-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 1F, prepare title compound (0.2g), with embodiment 40E alternate embodiment 1E.Use preparative HPLC to carry out purifying (on Phenomenex Luna C8 (2) 5 μ m 100 AXIA posts (30mm * 75mm)).Use the gradient of acetonitrile (A) and 0.1% trifluoroacetic acid/water (B), flow velocity 50 mL/min (0-0.5 min, 10% A; 0.5-7.0 min linear gradient, 10-95% A; 7.0-10.0 min, 95% A; 10.0-12.0 min linear gradient, 95-10% A). 1H NMR(300 MHz, DMSO-d 6)δ 2.42(s, 3 H)2.80-3.06(m, 5 H)3.08-3.31(m, 2 H)3.54(d, J=11.87 Hz, 2 H)3.69-3.93(m, 2 H)6.99-7.15(m, 3 H)7.34(d, J=6.78 Hz, 1 H)7.42-7.51(m, 1 H)7.53(s, 1 H)7.64-7.82(m, 3 H)9.08(s, 1 H)9.67(s, 1 H)10.65(s, 1 H)。MS(ESI +)m/z 501.2(M+H) +。
Embodiment 41
4-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino }-N-phenylcyclohexane methane amide
Embodiment 41A
4-[4-(the chloro-phenyl of 2-)-5-oxo-4,5-dihydro-3,4,7,9,9b-pentaaza-cyclopenta [a] naphthalene-8-base is amino]-phenylformic acid
In Biotage microwave reactor, by embodiment 1E (200.0 mg, 0.556 mmol), the mixture of PABA tertiary butyl ester (129 mg, 0.667 mmol) and dense HCl (0.08 mL, 2.63 mmol) heats 30 minutes at 160 ℃.Decant goes out solvent.By remaining resistates water treatment, supersound process, filters, and washes with water, dry by bake oven, and the HCl salt of title compound is provided.
Embodiment 41B
4-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino }-N-phenylcyclohexane methane amide
By embodiment 41A (60.0 mg, 0.128 mmol), 1-ethyl-3-[3-(dimethylamino) propyl group]-carbodiimide hydrochloride (36.8 mg, 0.192 mmol), I-hydroxybenzotriazole hydrate (29.4 mg, 0.192 mmol), triethylamine (0.071 mL, 0.511 mmol) and hexahydroaniline (0.022 mL, 0.192 mmol) mixture in DMF (2 mL) stirs 24 hours.Water is joined in this reaction soln.Cross filter solid, wash with water, dry by bake oven, title compound is provided. 1H NMR(400 MHz, DMSO-d 6)δ 1.20-1.09(m, 2H), 1.43-1.23(m, 4H), 1.62(d, J=12.3 Hz, 1H), 1.93-1.67(m, 4H), 3.84-3.74(m, 1H), 7.10(t, J=3.8 Hz, 1H), 7.67-7.51(m, 3H), 7.76-7.69(m, 1H), 7.99-7.84(m, 5H), 8.10(d, J=7.9 Hz, 1H), 9.18(s, 1H)。MS(ESI +)m/z 514.2(M+H) +。
Embodiment 42
6-(2-chloro-phenyl-)-2-(4-[(4-methylpiperazine-1-yl) and carbonyl] phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
By embodiment 41A (60.0 mg, 0.128 mmol), benzotriazole-1-base oxygen tripyrrole alkane Ji Phosphonium hexafluorophosphate (100 mg, 0.192 mmol), triethylamine (0.071 mL, 0.511 mmol) and 1-methylpiperazine (0.021 mL, 0.192 mmol) mixture in DMF (2 mL) stirs 5 hours.With 20% salt solution, dilute this reaction mixture, by ethyl acetate, extract (twice).The organic layer merging with 20% salt water washing, uses MgSO 4dry, filter, concentrated.With HPLC, purify resistates (referring to the scheme of embodiment 1F), the trifluoroacetate of title compound is provided. 1H NMR(400 MHz, CD 3OD)δ 2.96(s, 3H), 3.60-3.14(m, 6H), 4.56-4.31(m, 2H), 7.07(d, J=1.9 Hz, 1H), 7.63-7.54(m, 5H), 7.73-7.66(m, 1H), 7.90(d, J=1.9 Hz, 1H), 8.00-7.94(m, 2H), 9.18(s, 1H)。MS(ESI +)m/z 515.2(M+H) +。
Embodiment 43
6-(2-chloro-phenyl-)-2-{[4-(1H-pyrazoles-4-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 43A
8-(the bromo-phenyl amino of 4-)-4-(the chloro-phenyl of 2-)-4H-3,4,7,9,9b-pentaaza-cyclopenta [a] naphthalene-5-ketone
The mixture of embodiment 1E (250.0 mg, 0.695 mmol) and 4-bromaniline (191 mg, 1.112 mmol) is heated 1 hour at 90 ℃.When maintenance is warm, by the saturated NaHCO of resistates 3the aqueous solution is processed, and extracts (twice) by ethyl acetate.Use MgSO 4the dry organic layer merging, filters, concentrated.Resistates is ground with together with a small amount of ethyl acetate.Cross filter solid, with ethyl acetate/hexane washing, dry by bake oven, title compound is provided.
Embodiment 43B
6-(2-chloro-phenyl-)-2-{[4-(1H-pyrazoles-4-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
In Biotage microwave reactor, by embodiment 43A (45.0 mg, 0.096 mmol), 1-boc-pyrazoles-4-boric acid pinacol ester (31.1 mg, 0.106 mmol), two (triphenylphosphine) palladium chloride (II) (3.38 mg, 4.81 μ mol) and 1M sodium carbonate (0.077 mL, 0.077 mmol) mixture in glycol dimethyl ether/ethanol/water (7:2:3,1.2 mL) heats 15 minutes at 150 ℃.Evaporating solvent, purifies resistates (referring to the scheme of embodiment 1F) with HPLC, and the trifluoroacetate of title compound is provided. 1H NMR(400 MHz, DMSO-d 6)δ 7.09(d, J=1.8 Hz, 1H), 7.75-7.54(m, 7H), 7.90-7.78(m, 3H), 8.05(s, 2H), 9.13(s, 1H), 10.80(bs, 1H)。MS(ESI +)m/z 455.1(M+H) +。
Embodiment 44
6-(2-chloro-phenyl-)-2-(4-[2-(diethylamino) oxyethyl group] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 1F, prepare title compound, with 4-(2-(diethylamino) oxyethyl group) aniline, substitute 4-(4-methylpiperazine-1-yl) aniline. 1H NMR(400 MHz, CD 3OD)δ 1.44-1.29(m, 6H), 3.45-3.33(m, 4H), 3.66-3.60(m, 2H), 4.38(t, J=4.7 Hz, 2H), 7.12-7.03(m, 3H), 7.62-7.53(m, 3H), 7.89-7.66(m, 4H), 9.10(bs, 1H)。MS(ESI +)m/z 504.1(M+H) +。
Embodiment 45
6-(2-chloro-phenyl-)-2-{[4-(pyridin-3-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 43B, prepare title compound, with pyridin-3-yl boric acid, substitute 1-boc-pyrazoles-4-boric acid pinacol ester. 1H NMR(500 MHz, CD 3OD)δ 7.09(d, J=1.9 Hz, 1H), 7.62-7.52(m, 3H), 7.73-7.67(m, 1H), 7.96-7.87(m, 3H), 8.16-8.06(m, 3H), 8.78(d, J=5.6 Hz, 1H), 8.93-8.87(m, 1H), 9.19(bs, 1H), 9.22(s, 1H)。MS(ESI +)m/z 466.2(M+H) +。
Embodiment 46
4-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino }-N-(trans-4-hydroxy-cyclohexyl) benzamide
As described in embodiment 41B, prepare title compound, with trans-4-amino hexalin HCl displaced loop hexylamine. 1H NMR(400 MHz, DMSO-d 6)δ 1.31(dq, J=23.1, 10.3 Hz, 4H), 1.84(t, J=13.1 Hz, 4H), 3.17(s, 2H), 3.45-3.37(m,1H), 3.79-3.67(m, 1H), 7.09(t, J=2.1 Hz, 1H), 7.67-7.49(m, 3H), 7.74-7.71(m, 1H), 7.92(q, J=8.8 Hz, 4H), 8.08(d, J=7.9 Hz, 1H), 9.20(s, 1H), 10.96(s, 1H)。MS(ESI +)m/z 530.2(M+H) +。
Embodiment 47
4-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino }-N-ethyl benzamide
As described in embodiment 41B, prepare title compound, with ethamine displaced loop hexylamine. 1H NMR(400 MHz, DMSO-d 6)δ 1.14(t, J=7.2 Hz, 3H), 3.35-3.25(m, 2H), 7.12-7.07(m, 1H), 7.67-7.52(m, 4H), 7.76-7.68(m, 1H), 7.98-7.87(m, 4H), 8.39(t, J=5.5 Hz, 1H), 9.19(s, 1H), 10.97(bs, 1H)。MS(ESI +)m/z 460.2(M+H) +。
Embodiment 48
6-(2-chloro-phenyl-)-2-(4-[(4-hydroxy piperidine-1-yl) and carbonyl] phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 42, prepare title compound, with piperidines-4-alcohol, substitute 1-methylpiperazine. 1H NMR(400 MHz, CD 3OD)δ 1.63-1.44(m, 2H), 2.02-1.81(m, 2H), 3.43-3.28(m, 2H), 3.85-3.70(m, 1H), 3.97-3.86(m, 1H), 4.26-4.10(m, 1H), 7.08(d, J=1.9 Hz, 1H), 7.49(d, J=8.4 Hz, 2H), 7.62-7.53(m, 3H), 7.73-7.66(m, 1H), 7.99-7.86(m, 3H), 9.19(s, 1H)。MS(ESI +)m/z 516.2(M+H) +。
Embodiment 49
4-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino }-N-(pyridin-4-yl) benzamide
By embodiment 41A (60.0 mg, 0.128 mmol), pyridine-4-amine (18.05 mg, 0.192 mmol), triethylamine (0.071 mL, 0.511 mmol) and O-(7-azepine benzo triazol-1-yl)-N, N, N', N'-tetramethyl-urea hexafluorophosphate (72.9 mg, 0.192 mmol) mixture in DMF (2 mL) stirs 3.5 hours.Water is joined in this mixture.Solid filtering by forming, washes with water, with HPLC, purifies (referring to the scheme of embodiment 1F), and the trifluoroacetate of title compound is provided. 1H NMR(400 MHz, CD 3OD)δ 7.08(d, J=1.9 Hz, 1H), 7.63-7.51(m, 3H), 7.72-7.65(m, 1H), 7.90(d, J=1.9 Hz, 1H), 8.10-8.00(m, 4H), 8.41-8.34(m, 2H), 8.67-8.61(m, 2H), 9.21(s, 1H)。MS(ESI +)m/z 509.2(M+H) +。
Embodiment 50
6-(2-chloro-phenyl-)-2-(4-[3-(diethylamino) propoxy-] and-3-fluorophenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 1F, prepare title compound, with 4-(3-(diethylamino) propoxy-)-3-fluoroaniline, substitute 4-(4-methylpiperazine-1-yl) aniline. 1H NMR(400 MHz, CD 3OD)δ 1.36(t, J=7.3 Hz, 6H), 2.29-2.18(m, 2H), 3.33-3.27(m, 4H), 3.44-3.36(m, 2H), 4.20(t, J=5.6 Hz, 2H), 7.20-7.05(m, 2H), 7.63-7.51(m, 4H), 7.83-7.66(m, 3H), 9.14(bs, 1H)。MS(ESI +)m/z 536.0(M+H) +。
Embodiment 51
6-(2-chloro-phenyl-)-2-(the fluoro-4-[2-of 3-(4-methylpiperazine-1-yl) oxyethyl group] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 1F, prepare title compound, with the fluoro-4-of 3-(2-(4-methylpiperazine-1-yl) oxyethyl group) aniline, substitute 4-(4-methylpiperazine-1-yl) aniline. 1H NMR(400 MHz, CD 3OD)δ 2.90(s, 3H), 3.23-3.16(m, 6H), 3.44-3.35(m, 4H), 4.31(t, J=4.9 Hz, 2H), 7.08(d, J=1.9 Hz, 1H), 7.21-7.14(m, 1H), 7.63-7.53(m, 4H), 7.84-7.66(m, 3H), 9.15(bs, 1H)。MS(ESI +)m/z 549.2(M+H) +。
Embodiment 52
6-(2-chloro-phenyl-)-2-{[2-(2-methoxy ethyl)-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 21 (0.050 g, 0.074 mmol), triethylamine (0.070 mL) and the mixture of the bromo-2-methyl ethyl ether of 1-(40 μ l) in tetrahydrofuran (THF) (1.5 mL) are spent the night 65 ℃ of stirrings.Concentrated this reaction mixture, purifies (referring to the scheme of embodiment 1F) with HPLC, and the trifluoroacetate of title compound is provided. 1H NMR(400 MHz, CD 3OD)δ 3.27-3.08(m, 2H), 3.45(s, 3H), 3.58-3.50(m, 2H), 3.95-3.77(m, 4H), 4.71-4.44(m, 2H), 7.07(d, J=1.9 Hz, 1H), 7.33(d, J=8.2 Hz, 1H), 7.62-7.51(m, 3H), 7.74-7.65(m, 2H), 7.77(s, 1H), 7.87(d, J=1.5 Hz, 1H), 9.17(s, 1H)。MS(ESI +)m/z 502.1(M+H) +。
Embodiment 53
6-(2-chloro-phenyl-)-2-[(2,4,4-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-7-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 1F, prepare title compound, with 2,4,4-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-7-amine substitutes 4-(4-methylpiperazine-1-yl) aniline. 1H NMR(400 MHz, CD 3OD)δ 1.48(s, 6H), 3.12(s, 3H), 3.58-3.34(m, 4), 4.61-4.40(m, 4H), 7.07(d, J=1.9 Hz, 1H), 7.62-7.53(m, 4H), 7.77-7.66(m, 3H), 7.88(d, J=1.9 Hz, 1H), 9.17(s, 1H)。MS(ESI +)m/z 486.2(M+H) +。
Embodiment 54
6-(3-hydroxy-2-methyl phenyl)-2-(phenyl amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 54A
3-(3-methoxyl group-2-aminomethyl phenyl)-7-(methylthio group) Kui Linpyrimido quinoline [4,5-d] pyrimidine-2,4 (1H, 3H)-diketone
Preparation Example 54A as described in embodiment 1A (0.48 g), substitutes the chloro-2-isocyanato of 1-benzene by 1-isocyanato-3-methoxyl group-2-methylbenzene.MS(ESI +)m/z 331.1(M+H) +。
Embodiment 54B
The chloro-3-of 2-(3-methoxyl group-2-aminomethyl phenyl)-7-(methylthio group) Kui Linpyrimido quinoline [4,5-d] pyrimidine-4 (3H)-one
As described in embodiment 1B, prepare title compound (0.5 g), with embodiment 54A alternate embodiment 1A.MS(ESI +)m/z 349.0(M+H) +。
Embodiment 54C
2-(2,2-dimethoxy-ethyl is amino)-3-(3-methoxyl group-2-aminomethyl phenyl)-7-(methylthio group) Kui Linpyrimido quinoline [4,5-d] pyrimidine-4 (3H)-one
As described in embodiment 1C, prepare title compound (0.59 g), with embodiment 54B alternate embodiment 1B.MS(ESI +)m/z 417.1(M+H) +。
Embodiment 54D
4-(3-methoxyl group-2-methyl-phenyl)-8-methyl sulfenyl-4H-3,4,7,9,9b-pentaaza-cyclopenta [a] naphthalene-5-ketone
As described in embodiment 1D, prepare title compound (0.47g), with embodiment 54C alternate embodiment 1C.MS(ESI +)m/z 354.2(M+H) +。
Embodiment 54E
8-methanesulfinyl-4-(3-methoxyl group-2-methyl-phenyl)-4H-3,4,7,9,9b-pentaaza-cyclopenta [a] naphthalene-5-ketone
As described in embodiment 1E, prepare title compound (0.14g), with embodiment 54D alternate embodiment 1D.MS(ESI +)m/z 370.18(M+H) +。
Embodiment 54F
As described in embodiment 1F, prepare title compound (0.075 g), with aniline, substitute 4-(4-methylpiperazine-1-yl) aniline, with embodiment 54E alternate embodiment 1E.MS(ESI +)m/z 399.2(M+H) +。
Embodiment 54G
6-(3-hydroxy-2-methyl phenyl)-2-(phenyl amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
In the 2 mL methylene dichloride suspension of embodiment 54F (70 mg, 0.176 mmol), add boron trifluoride-dimethyl sulphide (0.129 mL, 1.230 mmol).Stir this reaction and spend the night, use methyl alcohol cancellation, concentrated.On Analogix 280, carry out chromatographic separation, use SF 12-24 post, use 35-100% ethyl acetate/hexane gradient elution 30 minutes, title compound is provided. 1H NMR(300 MHz, DMSO-d 6)δ 1.68-1.97(m, 3 H)6.78(d, J=6.74 Hz, 1 H)6.93(d, J=7.93 Hz, 1 H)7.05(d, J=1.59 Hz, 1 H)7.07-7.20(m, 2 H)7.42(t, J=7.93 Hz, 2 H)7.71-7.98(m, 3 H)9.11(s, 1 H)9.64(s, 1 H)10.69(s, 1 H)。MS(ESI +)m/z 385.2(M+H) +。
Embodiment 55
6-(2,6-dichlorophenyl)-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 55A
3-(2,6-dichlorophenyl)-7-(methylthio group) Kui Linpyrimido quinoline [4,5-d] pyrimidine-2,4 (1H, 3H)-diketone
As described in embodiment 1A, prepare title compound (10 g), with the chloro-2-isocyanato of 1,3-bis-benzene, substitute the chloro-2-isocyanato of 1-benzene.MS(ESI +)m/z 355.19(M+H) +。
Embodiment 55B
The chloro-3-of 2-(2,6-dichlorophenyl)-7-(methylthio group) Kui Linpyrimido quinoline [4,5-d] pyrimidine-4 (3H)-one
As described in embodiment 1B, prepare title compound (5.4 g), with embodiment 55A alternate embodiment 1A.MS(ESI +)m/z 372.54(M+H) +。
Embodiment 55C
3-(2,6-dichlorophenyl)-2-(2,2-dimethoxy-ethyl is amino)-7-(methylthio group) Kui Linpyrimido quinoline [4,5-d] pyrimidine-4 (3H)-one
As described in embodiment 1C, prepare title compound (6.4 g), with embodiment 55B alternate embodiment 1B.MS(ESI +)m/z 442.19(M+H) +。
Embodiment 55D
4-(the chloro-phenyl of 2,6-bis-)-8-methyl sulfenyl-4H-3,4,7,9,9b-pentaaza-cyclopenta [a] naphthalene-5-ketone
As described in embodiment 1D, prepare title compound (4.6g), with embodiment 55C alternate embodiment 1C.MS(ESI +)m/z 378.2(M+H) +。
Embodiment 55E
4-(the chloro-phenyl of 2,6-bis-)-8-methanesulfinyl-4H-3,4,7,9,9b-pentaaza-cyclopenta [a] naphthalene-5-ketone
As described in embodiment 1E, prepare title compound (0.5g), with embodiment 55D alternate embodiment 1D.MS(ESI +)m/z 370.18(M+H) +。
Embodiment 55F
6-(2,6-dichlorophenyl)-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 1F, prepare title compound (0.06g), with embodiment 55E alternate embodiment 1E.Use preparative HPLC to carry out purifying (on Phenomenex Luna C8 (2) 5 μ m 100 AXIA posts (30mm * 75mm)).Use the gradient of acetonitrile (A) and 0.1% trifluoroacetic acid/water (B), flow velocity 50 mL/min (0-0.5 min, 10% A; 0.5-7.0 min linear gradient, 10-95% A; 7.0-10.0 min, 95% A; 10.0-12.0 min linear gradient, 95-10% A). 1H NMR(300 MHz, DMSO-d 6) δ 2.80-3.05(m, 5 H)3.19(d, J=11.53 Hz, 2 H)3.46-3.61(m, 4 H)6.88-7.29(m, 3 H)7.42-7.99(m, 6 H)9.12(s, 1 H)9.62(s, 1 H)10.77(s, 1 H)。MS(ESI +)m/z 521.2(M+H) +。
Embodiment 56
2-[(4-aminophenyl) amino]-6-(2-chloro-phenyl-) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 56A
4,7,9,9b-pentaaza-cyclopenta [a] naphthalene-8-base is amino for 4-[4-(the chloro-phenyl of 2-)-5-oxo-4,5-dihydro-3] and-phenyl }-carboxylamine tertiary butyl ester
In the phial of adding a cover, the mixture of embodiment 1E (330.0 mg, 0.917 mmol) and 4-aminophenyl carboxylamine tertiary butyl ester (306 mg, 1.468 mmol) is heated 1 hour at 100 ℃.Resistates is dissolved in ethyl acetate, and uses saturated NaHCO 3solution washing.By organic layer MgSO 4dry, filter, concentrated, purifying on 40 g posts, is used ISCO Companion flash chromatographic system, with hexane/ethyl acetate (5:5 to 4:6) wash-out, provides title compound.
Embodiment 56B
2-[(4-aminophenyl) amino]-6-(2-chloro-phenyl-) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
By embodiment 56A (0.260 g, 0.516 mmol) and trifluoroacetic acid (0.397 mL, 5.16 mmol) at CH 2cl 2mixture in (5 mL) stirs 4 hours at 40 ℃.Concentrated this reaction mixture, purifies (referring to the scheme of embodiment 1F) with HPLC, and the trifluoroacetate of title compound is provided.By the saturated NaHCO of salt 3the aqueous solution is processed, and then filters, dry, obtains the free alkali form of title compound. 1H NMR(400 MHz, DMSO-d 6)δ 3.96(s, 2H), 7.09(d, J=1.8 Hz, 1H), 7.38-7.23(m, 2H), 7.66-7.52(m, 3H), 7.76-7.69(m, 1H), 7.96-7.91(m, 3H), 9.16(s, 1H), 10.73-10.68(m, 1H)。MS(ESI +)m/z 404.2(M+H) +。
Embodiment 57
N-(4-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } phenyl) ethanamide
By embodiment 56B (35.0 mg, 0.087 mmol), acetic acid (7.44 μ l, 0.130 mmol), triethylamine (0.048 mL, 0.347 mmol) and O-(7-azepine benzo triazol-1-yl)-N, N, N', the mixture of N'-tetramethyl-urea hexafluorophosphate (49.4 mg, 0.130 mmol) in tetrahydrofuran (THF) (2 mL) stirs 4 hours.Concentrated this reaction mixture, purifies (referring to the scheme of embodiment 1F) with HPLC, and the trifluoroacetate of title compound is provided. 1H NMR(400 MHz, CD 3OD)δ 2.13(s, 3H), 7.11(d, J=1.9 Hz, 1H), 7.63-7.51(m,5H), 7.73-7.66(m, 3H), 7.87(s, 1H), 9.14(bs, 1H)。MS(ESI +)m/z 446.2(M+H) +。
Embodiment 58
N-(4-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } phenyl) cyclopentane formamide
As described in embodiment 57, prepare title compound, with cyclopentane-carboxylic acid, substitute acetic acid. 1H NMR(400 MHz, DMSO-d 6)δ 1.91-1.50(m, 8H), 2.82-2.74(m, 1H), 7.06(d, J=1.8 Hz, 1H), 7.87-7.53(m, 9H), 9.10(s, 1H), 9.88(s, 1H), 10.73(bs, 1H)。MS(ESI +)m/z 500.2(M+H) +。
Embodiment 59
N-(4-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } phenyl)-4-hydroxyl cyclohexane carboxamide
As described in embodiment 57, prepare title compound, with 4-hydroxyl naphthenic acid, substitute acetic acid. 1H NMR(400 MHz, CD 3OD)δ 1.40-1.26(m, 1H), 1.78-1.55(m, 3H), 2.15-1.78(m, 4H), 2.48-2.24(m, 1H), 3.61-3.51(m, 0.5H), 4.00-3.94(m, 0.5H), 7.12(t, J=1.7 Hz, 1H), 7.63-7.52(m, 5H), 7.73-7.67(m, 3H), 7.88(s, 1H), 9.14(bs, 1H)。MS(ESI +)m/z 530.2(M+H) +。
Embodiment 60
N-(4-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } phenyl)-1-methyl piperidine-4-methane amide
As described in embodiment 57, prepare title compound, with 1-methyl piperidine-4-formic acid, substitute acetic acid. 1H NMR(400 MHz, CD 3OD)δ 2.32-1.95(m, 4H), 2.74-2.64(m, 1H), 2.94-2.88(m, 3H), 3.07(td, J=13.0, 3.1 Hz, 2H), 3.66-3.58(m, 2H), 7.06(d, J=1.9 Hz, 1H), 7.64-7.52(m, 5H), 7.78-7.66(m, 3H), 7.87-7.78(m, 1H), 9.15(bs, 1H)。MS(ESI +)m/z 529.1(M+H) +。
Embodiment 61
N-(4-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } phenyl) pyridine-4-methane amide
As described in embodiment 57, prepare title compound, with γ-picolinic acid, substitute acetic acid. 1H NMR(400 MHz, DMSO-d 6)δ 7.08(d, J=1.8 Hz, 1H), 7.67-7.52(m, 3H), 7.74-7.71(m, 1H), 7.98-7.69(m, 7H), 8.87-8.81(m, 2H), 9.14(s, 1H), 10.61(s, 1H), 10.82(bs, 1H)。MS(ESI +)m/z 509.2(M+H) +。
Embodiment 62
6-(2,6-3,5-dimethylphenyl)-2-[(2'-methyl-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 62A
3-(2,6-3,5-dimethylphenyl)-7-(methylthio group) Kui Linpyrimido quinoline [4,5-d] pyrimidine-2,4 (1H, 3H)-diketone
As described in embodiment 1A, prepare title compound (0.21 g), with 1,3-dimethyl-2-isocyanato benzene, substitute the chloro-2-isocyanato of 1-benzene.MS(ESI +)m/z 315.14(M+H) +。
Embodiment 62B
The chloro-3-of 2-(2,6-3,5-dimethylphenyl)-7-(methylthio group) Kui Linpyrimido quinoline [4,5-d] pyrimidine-4 (3H)-one
As described in embodiment 1B, prepare title compound (0.41 g), with embodiment 62A alternate embodiment 1A.MS(ESI +)m/z 333.06(M+H) +。
Embodiment 62C
2-(2,2-dimethoxy-ethyl is amino)-3-(2,6-3,5-dimethylphenyl)-7-(methylthio group) Kui Linpyrimido quinoline [4,5-d] pyrimidine-4 (3H)-one
As described in embodiment 1C, prepare title compound (6.4 g), with embodiment 62B alternate embodiment 1B.MS(ESI +)m/z 401.71(M+H) +。
Embodiment 62D
4-(2,6-dimethyl-phenyl)-8-methyl sulfenyl-4H-3,4,7,9,9b-pentaaza-cyclopenta [a] naphthalene-5-ketone
As described in embodiment 1D, prepare title compound (0.4g), with embodiment 62C alternate embodiment 1C.MS(ESI +)m/z 337.6(M+H) +。
Embodiment 62E
4-(2,6-dimethyl-phenyl)-8-methylsulfinyl-4H-3,4,7,9,9b-pentaaza-cyclopenta [a] naphthalene-5-ketone
As described in embodiment 1E, prepare title compound (0.17g), with embodiment 62D alternate embodiment 1D.MS(ESI +)m/z 354.17(M+H) +。
Embodiment 62F
6-(2,6-3,5-dimethylphenyl)-2-[(2'-methyl-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 1F, prepare title compound (0.07 g), with 2'-methyl-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9] alternative 4-(4-methylpiperazine-1-yl) aniline of-7'-amine, with embodiment 62E alternate embodiment 1E.Use preparative HPLC to carry out purifying (on Phenomenex Luna C8 (2) 5 μ m 100 AXIA posts (30mm * 75mm)).Use the gradient of acetonitrile (A) and 0.1% trifluoroacetic acid/water (B), flow velocity 50 mL/min (0-0.5 min, 10% A; 0.5-7.0 min linear gradient, 10-95% A; 7.0-10.0 min, 95% A; 10.0-12.0 min linear gradient, 95-10% A). 1H NMR(300 MHz, DMSO-d 6) δ 0.78-1.48(m, 4 H)1.86-2.12(m, 6 H)2.96(d, J=4.36 Hz, 3 H)3.14-3.36(m, 1 H)3.45-3.69(m, 1 H)4.41-4.87(m, 2 H)6.95(d, J=8.33 Hz, 1 H)7.09(d, J=1.59 Hz, 1 H)7.20-7.28(m, 2 H)7.27-7.39(m, 1 H)7.57-7.88(m, 3 H)9.14(s, 1 H)10.25(s, 1 H)10.80(s, 1 H)。MS(ESI +)m/z 478.2(M+H) +。
Embodiment 63
2-(4-[4-(3-chlorobenzyl) piperazine-1-yl] and phenyl } amino)-6-(2-chloro-phenyl-) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 1F, prepare title compound, with 4-(4-(3-chlorobenzyl) piperazine-1-yl) aniline, substitute 4-(4-methylpiperazine-1-yl) aniline. 1H NMR(400 MHz, CD 3OD)δ 3.60-3.10(m, 8H), 4.42(s, 1H), 7.08-7.00(m, 3H), 7.61-7.46(m, 7H), 7.87-7.62(m, 4H), 9.07(bs, 1H)。MS(ESI +)m/z 597.1(M+H) +。
Embodiment 64
6-(2-chloro-phenyl-)-2-(4-[4-(2-methoxy ethyl) piperazine-1-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 1F, prepare title compound, with 4-(4-(2-methoxy ethyl) piperazine-1-yl) aniline, substitute 4-(4-methylpiperazine-1-yl) aniline. 1H NMR(500 MHz, CD 3OD)δ 3.22-3.09(m, 2H), 3.39-3.27(m, 2H), 3.48-3.42(m, 5H), 3.75-3.65(m, 2H), 3.77(t, J=5.0 Hz, 2H), 3.89-3.77(m, 2H), 7.10-7.02(m, 3H), 7.61-7.51(m, 3H), 7.90-7.65(m, 4H), 9.08(bs, 1H)。MS(ESI +)m/z 531.2(M+H) +。
Embodiment 65
6-(2-chloro-phenyl-)-2-{[3-methoxyl group-4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 1F, prepare title compound, with 3-methoxyl group-4-(4-methylpiperazine-1-yl) aniline, substitute 4-(4-methylpiperazine-1-yl) aniline. 1H NMR(500 MHz, CD 3OD)δ 2.98(s, 3H), 3.10-3.00(m, 2H), 3.37-3.23(m, 2H), 3.64-3.52(m, 4H), 3.91(s, 3H), 7.05-6.97(m, 1H), 7.07(d, J=1.7 Hz, 1H), 7.45-7.31(m, 1H), 7.47(d, J=2.3 Hz, 1H), 7.64-7.52(m, 3H), 7.71-7.68(m, 1H), 7.90-7.77(m, 1H), 9.11(s, 1H)。MS(ESI +)m/z 517.1(M+H) +。
Embodiment 66
6-(2-chloro-phenyl-)-2-(3-methoxyl group-4-[4-(third-2-yl) piperazine-1-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 1F, prepare title compound, with 4-(4-sec.-propyl piperazine-1-yl)-3-anisidine, substitute 4-(4-methylpiperazine-1-yl) aniline.Temperature of reaction is arranged on 100 ℃. 1H NMR(400 MHz, DMSO-d 6)δ 1.32(d, J=6.5 Hz, 6H), 2.56(s, 3H), 3.01-2.90(m, 2H), 3.26-3.13(m, 2H), 3.60-3.48(m, 5H), 7.11-6.97(m, 2H), 7.51-7.38(m, 1H), 7.66-7.40(m, 4H), 7.73-7.71(m, 1H), 7.78(s, 1H), 9.12(s, 1H), 9.41 bs, 1H), 10.72(bs, 1H)。MS(ESI +)m/z 545.2(M+H) +。
Embodiment 67
6-(2-chloro-phenyl-)-2-(3-methoxyl group-4-[2-(4-methylpiperazine-1-yl) oxyethyl group] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 1F, prepare title compound, with 3-methoxyl group-4-(2-(4-methylpiperazine-1-yl) oxyethyl group) aniline, substitute 4-(4-methylpiperazine-1-yl) aniline. 1H NMR(400 MHz, CD 3OD)δ 2.91(s, 3H), 3.43-3.33(m, 10H), 3.91(s, 3H), 4.28(t, J=4.9 Hz, 2H), 7.09-7.01(m, 2H), 7.39-7.25(m, 1H), 7.49(d, J=2.5 Hz, 1H), 7.63-7.53(m, 3H), 7.72-7.66(m, 1H), 7.98-7.78(m, 1H), 9.13(bs, 1H)。MS(ESI +)m/z 561.2(M+H) +。
Embodiment 68
6-(3-hydroxy phenyl)-2-(phenyl amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 68A
3-(3-(allyloxy) phenyl)-7-(methylthio group) Kui Linpyrimido quinoline [4,5-d] pyrimidine-2,4 (1H, 3H)-diketone
As described in embodiment 1A, prepare title compound (0.21 g), with 1-(allyloxy)-3-isocyanato benzene, substitute the chloro-2-isocyanato of 1-benzene.MS(ESI +)m/z 341(M-H) +。
Embodiment 68B
3-(3-(allyloxy) phenyl) the chloro-7-of-2-(methylthio group) Kui Linpyrimido quinoline [4,5-d] pyrimidine-4 (3H)-one
As described in embodiment 1B, prepare title compound (0.09 g), with embodiment 68A alternate embodiment 1A.MS(ESI +)m/z 361.14(M+H) +。
Embodiment 68C
3-(3-(allyloxy) phenyl)-2-(2,2-dimethoxy-ethyl is amino)-7-(methylthio group) Kui Linpyrimido quinoline [4,5-d] pyrimidine-4 (3H)-one
As described in embodiment 1C, prepare title compound (0.12 g), with embodiment 68B alternate embodiment 1B.MS(ESI +)m/z 429.1(M+H) +。
Embodiment 68D
4-(3-allyloxy-phenyl)-8-methyl sulfenyl-4H-3,4,7,9,9b-pentaaza-cyclopenta [a] naphthalene-5-ketone
As described in embodiment 1D, prepare title compound (0.4g), with embodiment 68C alternate embodiment 1C.MS(ESI +)m/z 366.17(M+H) +。
Embodiment 68E
4-(3-allyloxy-phenyl)-8-methylsulfinyl-4H-3,4,7,9,9b-pentaaza-cyclopenta [a] naphthalene-5-ketone
As described in embodiment 1E, prepare title compound (0.75g), with embodiment 68D alternate embodiment 1D.MS(ESI +)m/z 382.1(M+H) +。
Embodiment 68F
As described in embodiment 1F, prepare title compound (0.042 g), with aniline, substitute 4-(4-methylpiperazine-1-yl) aniline, with embodiment 68E alternate embodiment 1E.MS(ESI +)m/z 411.1(M+H) +。
Embodiment 68G
6-(3-hydroxy phenyl)-2-(phenyl amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 54G, prepare title compound (0.03 g), with embodiment 68F alternate embodiment 54F. 1H NMR(300 MHz, DMSO-d 6) δ 3.17(s, 1 H)6.77-6.96(m, 3 H)7.04-7.20(m, 2 H)7.27-7.48(m, 3 H)7.86(d, J=8.33 Hz, 3 H)9.12(s, 1 H)10.71(s, 1 H). . MS(ESI +)m/z 371.2(M+H) +。
Embodiment 69
6-(2-chloro-phenyl-)-2-[(4-aminomethyl phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
In the phial of adding a cover, the mixture of embodiment 1E (132.0 mg, 0.367 mmol) and para-totuidine (86 mg, 0.807 mmol) is heated 1 hour at 90 ℃.After cooling, by the saturated NaHCO of resistates 3the aqueous solution and brine treatment, and extract (twice) by ethyl acetate.By the organic layer MgSO of merging 4dry, filter, concentrated, purifying on 12 g posts, is used ISCO Companion flash chromatographic system, uses CH 2cl 2/ ethyl acetate (8:2 to 7:3) wash-out, provides title compound. 1H NMR(400 MHz, CDCl 3)δ 2.39(s, 3H), 7.08(d, J=1.8 Hz, 1H), 7.26-7.23(m, 2H), 7.49-7.47(m, 3H), 7.57-7.55(m, 2H), 7.66-7.61(m, 1H), 7.72-7.67(m, 1H), 7.88-7.72(m, 1H), 9.24(s, 1H)。MS(ESI +)m/z 403.2(M+H) +。
Embodiment 70
6-(2-chloro-phenyl-)-2-{[4-(piperidin-2-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
In the phial of adding a cover, the mixture of embodiment 1E (0.048 g, 0.133 mmol) and 2-(4-aminophenyl) piperidines-1-formic acid tertiary butyl ester (0.059 g, 0.213 mmol) is heated 1 hour at 120 ℃.By ethyl acetate, process this reaction mixture, and use saturated NaHCO 3washing.Use MgSO 4dry organic layer, filters, concentrated.Resistates is dissolved in to CH 2cl 2in (2 mL), and process with trifluoroacetic acid (0.103 mL, 1.334 mmol).This mixture is stirred 5 hours at 35 ℃, concentrated, with HPLC, purify (referring to the scheme of embodiment 1F), the trifluoroacetate of title compound is provided. 1H NMR(500 MHz, CD 3OD)δ 1.89-1.72(m, 2H), 2.16-1.96(m, 4H), 3.25-3.16(m, 1H), 3.51-3.43(m, 1H), 4.29-4.22(m, 1H), 7.08(d, J=1.9 Hz, 1H), 7.62-7.50(m, 5H), 7.72-7.66(m, 1H), 7.97-7.86(m, 3H), 9.19(s, 1H)。MS(ESI +)m/z 472.2(M+H) +。
Embodiment 71
6-(2-chloro-phenyl-)-2-{[4-(pyrrolidin-2-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
In adding a cover phial, the mixture of embodiment 1E (0.048 g, 0.133 mmol) and 2-(4-aminophenyl) tetramethyleneimine-1-formic acid tertiary butyl ester (0.056 g, 0.213 mmol) is heated 30 minutes at 130 ℃.By ethyl acetate, process this reaction mixture, and use saturated NaHCO 3solution washing.Use MgSO 4dry organic layer, filters, concentrated.Resistates is dissolved in to CH 2cl 2in (2 mL), and process with trifluoroacetic acid (0.103 mL, 1.334 mmol).This mixture is stirred and spent the night at 35 ℃, concentrated, with HPLC, purify (referring to the scheme of embodiment 1F), the trifluoroacetate of title compound is provided. 1H NMR(500 MHz, CD 3OD)δ 2.36-2.19(m, 3H), 2.57-2.47(m, 1H), 3.53-3.41(m, 2H), 4.69-4.62(m, 1H), 7.08(d, J=1.9 Hz, 1H), 7.62-7.51(m, 5H), 7.72-7.66(m, 1H), 7.88(d, J=1.9 Hz, 1H), 7.97-7.92(m, 2H), 9.19(s, 1H)。MS(ESI +)m/z 458.2(M+H) +。
Embodiment 72
6-(2-chloro-phenyl-)-2-{[4-(pyrrolidin-3-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
In adding a cover phial, the mixture of embodiment 1E (0.048 g, 0.133 mmol) and 3-(4-aminophenyl) tetramethyleneimine-1-formic acid tertiary butyl ester (0.056 g, 0.213 mmol) is heated 1 hour at 90 ℃.By ethyl acetate, process this reaction mixture, and use saturated NaHCO 3solution washing.Use MgSO 4dry organic layer, filters, concentrated.Resistates is dissolved in to CH 2cl 2in (2 mL), and process with trifluoroacetic acid (0.103 mL, 1.334 mmol).This mixture is stirred 5 hours at 35 ℃, concentrated, with HPLC, purify (referring to the scheme of embodiment 1F), the trifluoroacetate of title compound is provided. 1H NMR(500 MHz, CD 3OD)δ 2.24-2.05(m, 1H), 2.49(dtd, J=10.2, 7.1, 3.1 Hz, 1H), 3.21(dd, J=24.8, 13.8 Hz, 1H), 3.46-3.37(m, 1H), 3.61-3.52(m, 2H), 3.73(dd, J=11.4, 7.9 Hz, 1H), 7.07(d, J=1.8 Hz, 1H), 7.40-7.39(m, 2H), 7.62-7.51(m, 3H), 7.73-7.66(m, 1H), 7.86-7.81(m, 3H), 9.15(s, 1H)。MS(ESI +)m/z 458.2(M+H) +。
Embodiment 73
6-(2,6-dichlorophenyl)-2-[(2'-methyl-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 1F, prepare title compound (0.02 g), with 2'-methyl-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9] alternative 4-(4-methylpiperazine-1-yl) aniline of-7'-amine, with embodiment 55E alternate embodiment 1E.Crude product is ground together with 1:1 DMSO/ methyl alcohol, filter high vacuum dry. 1H NMR(300 MHz, DMSO-d 6) δ 0.76-1.01(m, 4 H)2.27-2.38(m, 3 H)2.46(s, 2 H)3.63(s, 2 H)6.77(d, J=8.33 Hz, 1 H)7.11(d, J=1.59 Hz, 1 H)7.49(s, 1 H)7.56-7.69(m, 2 H)7.71-7.83(m, 3 H)9.14(s, 1 H)10.77(s, 1 H)MS(ESI+)m/z 518.1(M+H) +。
Embodiment 74
6-(2,6-dichlorophenyl)-2-{[3-methyl-4-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 1F, prepare title compound (0.04 g), with 3-methyl-4-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) aniline, substitute 4-(4-methylpiperazine-1-yl) aniline, with embodiment 55E alternate embodiment 1E.Use preparative HPLC to carry out purifying (on Phenomenex Luna C8 (2) 5 μ m 100 AXIA posts (30mm * 75mm)).Use the gradient of acetonitrile (A) and 0.1% trifluoroacetic acid/water (B), flow velocity 50 mL/min (0-0.5 min, 10% A; 0.5-7.0 min linear gradient, 10-95% A; 7.0-10.0 min, 95% A; 10.0-12.0 min linear gradient, 95-10% A). 1H NMR(300 MHz, DMSO-d 6) δ 2.00-2.22(m, 2 H)2.21-2.42(m, 5 H)2.91(d, J=4.76 Hz, 3 H)3.10(t, J=6.54 Hz, 2 H)3.21-3.36(m, 4 H)6.97-7.38(m, 2 H)7.38-7.99(m, 6 H)9.14(s, 1 H)9.51(s, 1 H)10.76(s, 1 H)。MS(ESI+)m/z 549.1(M+H) +。
Embodiment 75
6-(2-chloro-phenyl-)-2-{[4-(piperazine-1-yl)-3-(trifluoromethyl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
In the phial of adding a cover, by embodiment 1E (0.060 g, 0.167 mmol) and the mixture of 4-(4-amino-2-(trifluoromethyl) phenyl) piperazine-1-formic acid tertiary butyl ester (0.092 g, 0.267 mmol) at 130 ℃, heat 1 hour.By ethyl acetate, process this reaction mixture, and use saturated NaHCO 3solution washing.Use MgSO 4dry organic layer, filters, concentrated.By crude product purifying on 12 g posts, use ISCO Companion flash chromatographic system, use CH 2cl 2/ ethyl acetate (9:1 to 7:3) wash-out, obtains target intermediate.Intermediate is dissolved in to CH 2cl 2in (2 mL), and process with trifluoroacetic acid (0.128 mL, 1.668 mmol).This mixture is stirred 4 hours at 40 ℃, concentrated, with HPLC, purify (referring to the scheme of embodiment 1F), the trifluoroacetate of title compound is provided. 1H NMR(400 MHz, CD 3OD)δ 3.25-3.11(m, 4H), 3.47-3.33(m, 4H), 7.09(d, J=1.6 Hz, 1H), 7.64-7.42(m, 4H), 7.75-7.64(m, 1H), 7.83(s, 1H), 8.06(d, J=7.1 Hz, 1H), 8.37(bs, 1H), 9.21(s, 1H)。MS(ESI +)m/z 541.1(M+H) +。
Embodiment 76
6-(2-chloro-phenyl-)-2-(4-[(2S) and-pyrrolidin-2-yl methoxyl group] phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
In adding a cover phial, by embodiment 1E (0.060 g, 0.167 mmol) and the mixture of (S)-2-((4-amino-benzene oxygen) methyl) tetramethyleneimine-1-formic acid tertiary butyl ester (0.078 g, 0.267 mmol) at 90 ℃, heat 1 hour.By ethyl acetate, process this reaction mixture, and use saturated NaHCO 3solution washing.Use MgSO 4dry organic layer, filters, concentrated.By crude product purifying on 12 g posts, use ISCO Companion flash chromatographic system, use CH 2cl 2/ ethyl acetate (9:1 to 6:4) wash-out, obtains target intermediate.Intermediate is dissolved in to CH 2cl 2in (2 mL), and process with trifluoroacetic acid (0.128 mL, 1.668 mmol).This mixture is stirred 5 hours at 35 ℃, concentrated, with HPLC, purify (referring to the scheme of embodiment 1F), the trifluoroacetate of title compound is provided. 1H NMR(400 MHz, CD 3OD)δ 1.99-1.89(m, 1H), 2.21-2.03(m, 2H), 2.33-2.25(m, 1H), 3.3.40-3.34(m, 2H), 4.18-3.96(m, 2H), 4.37(dd, J=10.5, 3.3 Hz, 1H), 7.10-7.03(m, 3H), 7.62-7.53(m, 3H), 7.87-7.64(m, 4H), 9.12(s, 1H)。MS(ESI +)m/z 488.1(M+H) +。
Embodiment 77
6-(2-chloro-phenyl-)-2-(2-methyl-4-[3-(4-methylpiperazine-1-yl) propoxy-] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 1F, prepare title compound, with 2-methyl-4-(3-(4-methylpiperazine-1-yl) propoxy-) aniline, substitute 4-(4-methylpiperazine-1-yl) aniline.Temperature of reaction is arranged on 100 ℃. 1H NMR(400 MHz, CD 3OD)δ 2.31-2.12(m, 4H), 2.91(s, 3H), 3.22-3.13(m, 2H), 3.36-3.26(m, 2H), 3.49-3.38(m, 4H), 4.13(t, J=5.8 Hz, 2H), 6.93-6.79(m, 2H), 7.12-7.03(m, 1H), 7.46-7.23(m, 1H), 7.62-7.51(m, 3.5H), 7.72-7.65(m, 1H), 7.95-7.87(m, 0.5H), 9.15-8.95(m, 1H)。MS(ESI +)m/z 559.2(M+H) +。
Embodiment 78
6-(2-chloro-phenyl-)-2-{[4-(morpholine-4-ylmethyl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
In adding a cover phial, the mixture of embodiment 1E (0.060 g, 0.167 mmol) and 4-(morpholino methyl) aniline (0.051 g, 0.267 mmol) is heated 1 hour at 90 ℃.With HPLC, purify crude product (referring to the scheme of embodiment 1F).By the saturated NaHCO of tfa salt 3the aqueous solution is processed, and extracts in ethyl acetate.By organic layer MgSO 4dry, filter, concentrated, purifying on 12 g posts, is used ISCO Companion flash chromatographic system, with methanol/ethyl acetate (5:95 to 10:90) wash-out, provides title compound. 1H NMR(400 MHz, CD 3OD)δ 2.56-2.39(m, 4H), 3.54(s, 2H), 3.73-3.67(m, 4H), 7.05(d, J=1.9 Hz, 1H), 7.43-7.36(m, 2H), 7.61-7.52(m, 3H), 7.70-7.67(m, 1H), 7.80-7.73(m, 2H),7.86(s, 1H), 9.15(s, 1H)。MS(ESI +)m/z 488.0(M+H) +。
Embodiment 79
6-(2-chloro-phenyl-)-2-{[4-(1H-imidazoles-1-ylmethyl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
In adding a cover phial, the mixture of embodiment 1E (0.060 g, 0.167 mmol) and 4-((1H-imidazoles-1-yl) methyl) aniline (0.046 g, 0.267 mmol) is heated 1 hour at 100 ℃.By ethyl acetate, process this reaction mixture, and use saturated NaHCO 3solution washing.Use MgSO 4dry organic layer, filters, concentrated.By crude product purifying on 12 g posts, use ISCO Companion flash chromatographic system, with methanol/ethyl acetate (5:95 to 10:90) wash-out, provide title compound. 1H NMR(400 MHz, CD 3OD)δ 5.23(s, 2H), 7.00(s, 1H), 7.04(d, J=1.9 Hz, 1H), 7.14(s, 1H), 7.35-7.29(m, 2H), 7.61-7.51(m, 3H), 7.71-7.64(m, 1H), 7.87-7.75(m, 4H), 9.14(s, 1H)。MS(ESI +)m/z 468.8(M+H) +。
Embodiment 80
6-(2-chloro-phenyl-)-2-{[4-(1H-imidazoles-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 1F, prepare title compound, with 4-(1H-imidazoles-1-yl) aniline, substitute 4-(4-methylpiperazine-1-yl) aniline.Temperature of reaction is arranged on 100 ℃. 1H NMR(400 MHz, CD 3OD)δ 7.09(d, J=1.8 Hz, 1H), 7.63-7.50(m, 3H), 7.72-7.66(m, 1H), 7.79-7.77(m, 3H), 7.93(d, J=1.9 Hz, 1H), 8.09(t, J=1.7 Hz, 1H), 8.13(d, J=8.9 Hz, 2H), 9.24(s, 1H), 9.46(s, 1H)。MS(ESI +)m/z 455.2(M+H) +。
Embodiment 81
6-(2-chloro-phenyl-)-2-{[6-(piperazine-1-yl) pyridin-3-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
In adding a cover phial, the mixture of embodiment 1E (0.060 g, 0.167 mmol) and 4-(5-aminopyridine-2-yl) piperazine-1-formic acid tertiary butyl ester (0.074 g, 0.267 mmol) is heated 1 hour at 100 ℃.By ethyl acetate, process this reaction mixture, and use saturated NaHCO 3solution washing.Dry organic layer, filters, concentrated.By crude product purifying on 12 g posts, use ISCO Companion flash chromatographic system, with hexane/ethyl acetate (2:8 to 1:9) wash-out, obtain target intermediate.Intermediate is dissolved in to CH 2cl 2in (2 mL), and process with trifluoroacetic acid (0.128 mL, 1.668 mmol).This reaction mixture is stirred 2.5 hours at 40 ℃, concentrated, with HPLC, purify (referring to the scheme of embodiment 1F), the trifluoroacetate of title compound is provided. 1H NMR(400 MHz, CD 3OD)δ 3.41-3.38(m, 4H), 3.90-3.83(m, 4H), 7.08(d, J=1.9 Hz, 1H), 7.21-7.14(m, 1H), 7.63-7.53(m, 3H), 7.73-7.66(m, 1H), 7.90-7.82(m, 1H), 8.16(dd, J=9.2, 2.7 Hz, 1H), 8.75-8.58(m, 1H), 9.16(s, 1H)。MS(ESI +)m/z 474.2(M+H) +。
Embodiment 82
6-(2-chloro-phenyl-)-2-(3-[3-(4-methylpiperazine-1-yl) propoxy-] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 1F, prepare title compound, with 3-(3-(4-methylpiperazine-1-yl) propoxy-) aniline, substitute 4-(4-methylpiperazine-1-yl) aniline.Temperature of reaction is arranged on 100 ℃. 1H NMR(400 MHz, CD 3OD)δ 2.25-2.12(m, 2H), 2.90(s, 3H), 3.19(t, J=7.5 Hz, 2H), 3.35-3.27(m, 4H), 3.53-3.42(m, 4H), 4.16(t, J=5.8 Hz, 2H), 6.75(d, J=6.5 Hz, 1H), 7.08(d, J=1.9 Hz, 1H), 7.41-7.24(m, 2H), 7.63-7.49(m, 4H), 7.73-7.66(m, 1H), 7.85(s, 1H), 9.17(s, 1H)。MS(ESI +)m/z 545.3(M+H) +。
Embodiment 83
6-(2-chloro-phenyl-)-2-(3-[3-(piperidin-1-yl) propoxy-] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
In Biotage microwave reactor, embodiment 1E (0.060 g, 0.167 mmol) and 3-(3-(piperidin-1-yl) propoxy-) aniline (0.047 g) and the mixture of dense HCl (3) in acetonitrile are heated 20 minutes at 170 ℃.Concentrated this reaction mixture, purifies (referring to the scheme of embodiment 1F) with HPLC, and the trifluoroacetate of title compound is provided. 1H NMR(400 MHz, CD 3OD)δ 1.91-1.45(m, 4H), 1.98(d, J=14.6 Hz, 2H), 2.27(td, J=11.3, 5.7 Hz, 2H), 2.98(dt, J=12.6, 6.3 Hz, 2H), 3.36-3.33(m, 2H), 3.63-3.59(m, 2H), 4.24-4.04(m, 2H), 6.75(d, J=6.7 Hz, 1H), 7.07(d, J=1.8 Hz, 1H), 7.32-7.27(m, 2H), 7.65-7.40(m, 4H), 7.73-7.64(m, 1H), 7.84(s, 1H), 9.16(s, 1H)。MS(ESI +)m/z 530.2(M+H) +。
Embodiment 84
6-(2,6-dichlorophenyl)-2-(phenyl amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 1F, prepare title compound (0.025g), with aniline, substitute 4-(4-methylpiperazine-1-yl) aniline, with embodiment 55E alternate embodiment 1E.With Analogix 280 (SF 12-24 post), carry out chromatographic separation, use 15% to 75% ethyl acetate/hexane gradient elution 30 minutes. 1H NMR(300 MHz, DMSO-d 6) δ 7.08-7.21(m, 2 H)7.43(t, J=7.80 Hz, 2 H)7.59-7.68(m, 1 H)7.72-7.79(m, 2 H)7.86(s, 3 H)9.17(s, 1 H)10.69-10.97(m, J=8.14 Hz, 1 H)。MS(ESI+)m/z 423.2(M+H) +。
Embodiment 85
6-(2-chloro-phenyl-)-2-(3-methoxyl group-4-[2-(third-2-base is amino) oxyethyl group] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 81, prepare title compound, by 2-(4-amino-2-methoxyphenoxy) ethyl (sec.-propyl) carboxylamine tertiary butyl ester, substitute 4-(5-aminopyridine-2-yl) piperazine-1-formic acid tertiary butyl ester.The movement of post is CH mutually fast 2cl 2/ ethyl acetate (8:2 to 7:3). 1H NMR(400 MHz, CD 3OD)δ 1.40(d, J=6.5 Hz, 6H), 3.45(t, J=4.7 Hz, 2H), 3.55-3.48(m, 1H), 3.94(s, 3H), 4.30-4.24(m, 2H), 7.09-7.02(m, 2H), 7.40-7.25(m, 1H), 7.64-7.50(m, 4H), 7.71-7.68(m, 1H), 7.80(bs, 1H), 9.12(bs, 1H)。MS(ESI +)m/z 520.2(M+H) +。
Embodiment 86
6-(2-chloro-phenyl-)-2-(the chloro-4-[2-of 3-(third-2-base is amino) oxyethyl group] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 81, prepare title compound, by 2-(4-amino-2-chlorophenoxy) ethyl (sec.-propyl) carboxylamine tertiary butyl ester, substitute 4-(5-aminopyridine-2-yl) piperazine-1-formic acid tertiary butyl ester.The movement of post is CH mutually fast 2cl 2/ ethyl acetate (8:2 to 7:3). 1H NMR(400 MHz, CD 3OD)δ 1.41(d, J=6.5 Hz, 6H), 3.65-3.50(m, 3H), 4.37(t, J=4.8 Hz, 2H), 7.07(d, J=1.9 Hz, 1H), 7.24-7.17(m, 1H), 7.62-7.53(m, 3H), 7.70-7.68(m, 2H), 7.79(bs, 1H), 8.00(s, 1H), 9.15(bs, 1H)。MS(ESI +)m/z 524.1(M+H) +。
Embodiment 87
6-(2-chloro-phenyl-)-2-{[4-(methylol) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 1F, prepare title compound, with (4-aminophenyl) methyl alcohol, substitute 4-(4-methylpiperazine-1-yl) aniline.Temperature of reaction is arranged on 120 ℃. 1H NMR(400 MHz, DMSO-d 6)δ 4.50(s, 2H), 7.10-7.05(m, 1H), 7.38-7.36(m, 1H), 7.64-7.53(m, 4H), 7.73-7.69(m, 1H), 7.81(bs, 2H), 9.13(s, 1H), 10.75(s, 1H)。MS(ESI +)m/z 419.2(M+H) +。
Embodiment 88
6-(2-chloro-phenyl-)-2-{[4-(1H-pyrazol-1-yl methyl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 1F, prepare title compound, with 4-((1H-pyrazol-1-yl) methyl) aniline, substitute 4-(4-methylpiperazine-1-yl) aniline.Temperature of reaction is arranged on 100 ℃. 1H NMR(400 MHz, DMSO-d 6)δ 5.33(s, 2H), 6.28(t, J=2.0 Hz, 1H), 7.07(d, J=1.8 Hz, 1H), 7.32-7.26(m, 2H), 7.47(d, J=1.8 Hz, 1H), 7.66-7.51(m, 3H), 7.73-7.71(m, 1H), 7.87-7.76(m, 4H), 9.13(s, 1H), 10.79(bs, 1H)。MS(ESI +)m/z 469.2(M+H) +。
Embodiment 89
6-(2-chloro-phenyl-)-2-{[4-(1H-pyrazol-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 1F, prepare title compound, with 4-(1H-pyrazol-1-yl) aniline, substitute 4-(4-methylpiperazine-1-yl) aniline.Temperature of reaction is arranged on 100 ℃. 1H NMR(400 MHz, DMSO-d 6)δ 6.55(t, J=2.0 Hz, 1H), 7.09(d, J=1.8 Hz, 1H), 7.67-7.52(m, 3H), 7.75-7.71(m, 2H), 8.04-7.86(m, 5H), 8.46(d, J=2.5 Hz, 1H), 9.16(s, 1H), 10.91(bs, 1H)。MS(ESI +)m/z 455.2(M+H) +。
Embodiment 90
6-(2-chloro-phenyl-)-2-(2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-base amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
In adding a cover phial, by embodiment 1E (0.500 g, 1.390 mmol) and 7'-amino-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-2'(3'H) mixture of-formic acid tertiary butyl ester (0.610 g, 2.224 mmol) heats 1 hour at 100 ℃.By ethyl acetate, process this reaction mixture, and use saturated NaHCO 3solution washing.Use MgSO 4dry organic layer, filters, concentrated.By crude product purifying on 40 g posts, use ISCO Companion flash chromatographic system, with hexane/ethyl acetate (4:6 to 3:7) wash-out, obtain target intermediate.Intermediate is dissolved in to CH 2cl 2in (6 mL), and process with trifluoroacetic acid (0.857 mL, 11.12 mmol).This reaction mixture is stirred 2 hours at 35 ℃, concentrated, with HPLC, purify (referring to the scheme of embodiment 1F), the trifluoroacetate of title compound is provided. 1H NMR(400 MHz, CD 3OD)δ 1.17-1.12(m, 2H), 1.27-1.24(m, 2H), 3.37(s, 2H), 4.54(s, 2H), 6.99-6.91(m, 1H), 7.07(d, J=1.9 Hz, 1H), 7.63-7.53(m, 3H), 7.75-7.66(m, 3H), 7.87(bs, 1H), 9.16(s, 1H)。MS(ESI +)m/z 470.2(M+H) +。
Embodiment 91
2-[(2'-ethanoyl-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl) amino]-6-(2-chloro-phenyl-) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
By embodiment 90 (0.100 g, 0.143 mmol), acetic acid (0.012 mL, 0.215 mmol), benzotriazole-1-base oxygen tripyrrole alkane Ji Phosphonium hexafluorophosphate (0.112 g, 0.215 mmol) and tetrahydrofuran (THF) (5 mL) solution stirring of triethylamine (0.100 mL, 0.716 mmol) spend the night.The suspension obtaining is diluted by ethyl acetate, and use saturated NaHCO 3solution washing.By suspension filtered, concentrated.DMSO/ methyl alcohol (1:1) (containing several trifluoroacetic acids) for resistates is processed.By the saturated NaHCO of suspension 3aqueous solution dilution, filters, and washes with water, dry by bake oven, and title compound is provided. 1H NMR(400 MHz, DMSO-d 6)δ 1.13-0.91(m, 4H), 2.12(s, 1.7H), 2.20(s, 1.3H), 3.62-3.59(m, 2H), 4.89-4.79(m, 2H), 6.99-6.93(m, 1H), 7.14(t, J=2.1 Hz, 1H), 7.87-7.57(m, 7H), 9.18(s, 1H), 10.79(bs, 1H)。MS(ESI +)m/z 512.2(M+H) +。
Embodiment 92
6-(2-chloro-phenyl-)-2-[(1-methyl isophthalic acid, 2,3,4-tetrahydroquinoline-6-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 1F, prepare title compound, use 1-methyl isophthalic acid, 2,3,4-tetrahydroquinoline-6-amine substitutes 4-(4-methylpiperazine-1-yl) aniline.Temperature of reaction is arranged on 100 ℃. 1H NMR(400 MHz, CD 3OD)δ 2.27-2.17(m, 2H), 3.08-2.78(m, 2H), 3.24,(s, 3H), 3.64-3.50(m, 2H), 7.08(d, J=1.9 Hz, 1H), 7.50-7.29(m, 1H), 7.63-7.51(m, 3H), 7.73-7.66(m, 2H), 7.80(d, J=8.3 Hz, 1H), 7.86(d, J=1.9 Hz, 1H), 9.17(s, 1H)。MS(ESI +)m/z 458.2(M+H) +。
Embodiment 93
6-(2-chloro-phenyl-)-2-(1-[2-(dimethylamino) ethyl] and-2,3-dihydro-1H-indoles-5-yl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 1F, prepare title compound, with 1-(2-(dimethylamino) ethyl) indoline-5-amine, substitute 4-(4-methylpiperazine-1-yl) aniline.Temperature of reaction is arranged on 100 ℃. 1H NMR(400 MHz, CD 3OD)δ 2.98(s, 6H), 3.12-3.02(m, 2H), 3.55-3.37(m, 6H), 6.78-6.72(m, 1H), 7.05(d, J=1.8 Hz, 1H), 7.61-7.42(m, 5H), 7.88-7.66(m, 2H), 9.08(s, 1H)。MS(ESI +)m/z 501.2(M+H) +。
Embodiment 94
6-(2-chloro-phenyl-)-2-{[2-(dimethylamino)-2,3-dihydro-1H-indenes-5-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 1F, prepare title compound, use N 2, N 2-dimethyl-2,3-dihydro-1H-indenes-2,5-diamines substitutes 4-(4-methylpiperazine-1-yl) aniline.Temperature of reaction is arranged on 100 ℃. 1H NMR(400 MHz, CD 3OD)δ 2.95(s, 6H), 3.31-3.11(m, 2H), 3.61-3.39(m, 2H), 4.22-4.13(m, 1H), 7.06(d, J=1.9 Hz, 1H), 7.32(d, J=7.9 Hz, 1H), 7.63-7.51(m, 4H), 7.72-7.64(m, 1H), 7.87-7.81(m, 2H), 9.14(s, 1H)。MS(ESI +)m/z 472.2(M+H) +。
Embodiment 95
6-(the chloro-6-fluorophenyl of 2-)-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 95A
3-(the chloro-6-fluorophenyl of 2-)-7-(methylthio group) Kui Linpyrimido quinoline [4,5-d] pyrimidine-2,4 (1H, 3H)-diketone
As described in embodiment 1A, prepare title compound, with the fluoro-2-isocyanato of the chloro-3-of 1-benzene, substitute the chloro-2-isocyanato of 1-benzene (2 hours reaction times).
Embodiment 95B
The chloro-3-of 2-(the chloro-6-fluorophenyl of 2-)-7-(methylthio group) Kui Linpyrimido quinoline [4,5-d] pyrimidine-4 (3H)-one
By embodiment 95A (0.960 g, 2.83 mmol) at POCl 3mixture in (3.5 mL, 37.5 mmol) and diisopropylethylamine (DIEA) (3.5 mL, 20.04 mmol) heats 1.5 hours at 90 ℃.After concentrated this reaction mixture, by ice and NaHCO for resistates 3the aqueous solution is processed, and extracts by ethyl acetate.By organic layer MgSO 4dry, filter, concentrated, purifying on 40 g silica columns, is used ISCO Companion flash chromatographic system, with hexane/ethyl acetate (7:3 to 6:4) wash-out, provides title compound.
Embodiment 95C
4-(the chloro-6-fluorophenyl of 2-)-8-methyl sulfenyl-4H-3,4,7,9,9b-pentaaza-cyclopenta [a] naphthalene-5-ketone
As described in embodiment 1C and 1D, prepare title compound, in embodiment 1C, with embodiment 95B alternate embodiment 1B.In second step, by ethyl acetate, grind to replace quick post, by title compound purifying.
Embodiment 95D
4-(the chloro-6-fluorophenyl of 2-)-8-methanesulfinyl-4H-3,4,7,9,9b-pentaaza-cyclopenta [a] naphthalene-5-ketone
As described in embodiment 1E, prepare title compound, with embodiment 95C alternate embodiment 1D.
Embodiment 95E
6-(the chloro-6-fluorophenyl of 2-)-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
The mixture of embodiment 95D (0.060 g, 0.159 mmol) and 4-(4-methylpiperazine-1-yl) aniline (0.049 g, 0.254 mmol) is mixed, and at 100 ℃, heat 0.5 hour.With HPLC, purify crude product (referring to the scheme of embodiment 1F), the trifluoroacetate of title compound is provided. 1H NMR(400 MHz, CD 3OD)δ 2.98(s, 3H), 3.16-3.01(m, 2H), 3.36-3.21(m, 2H), 3.63-3.61(m, 2H), 3.87-3.84(m, 2H), 7.17-6.95(m, 3H), 7.38(dd, J=12.8, 4.7 Hz, 1H), 7.53(d, J=8.2 Hz, 1H), 7.97-7.57(m, 4H), 9.08(s, 1H)。MS(ESI +)m/z 505.2(M+H) +。
Embodiment 96
6-(the chloro-6-fluorophenyl of 2-)-2-{[3-methyl-4-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 95E, prepare title compound, with 3-methyl-4-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) aniline, substitute 4-(4-methylpiperazine-1-yl) aniline. 1H NMR(400 MHz, CD 3OD)δ 2.30-2.09(m, 2H), 2.41(s, 3H), 3.01(s, 3H), 3.48-3.17(m, 6H), 3.66-3.56(m, 2H), 7.08(d, J=1.9 Hz, 1H), 7.24-7.10(m, 1H), 7.43-7.34(m, 1H), 7.67-7.50(m, 4H), 7.90-7.76(m, 1H), 9.14(bs, 1H)。MS(ESI +)m/z 533.2(M+H) +。
Embodiment 97
6-(the chloro-6-fluorophenyl of 2-)-2-[(2,4,4-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-7-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 95E, prepare title compound, with 2,4,4-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-7-amine substitutes 4-(4-methylpiperazine-1-yl) aniline. 1H NMR(400 MHz, CD 3OD)δ 1.48(s, 6H), 3.12(s, 3H), 3.41-3.28(m, 1H), 3.61-3.49(m, 1H), 4.64-4.37(m, 2H), 7.09(d, J=1.8 Hz, 1H), 7.43-7.31(m, 1H), 7.68-7.50(m, 3H), 7.75(s, 2H), 7.89(d, J=1.7 Hz, 1H), 9.18(s, 1H)。MS(ESI +)m/z 504.2(M+H) +。
Embodiment 98
6-(2,6-difluorophenyl)-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 98A
3-(2,6-difluorophenyl)-7-(methylthio group) Kui Linpyrimido quinoline [4,5-d] pyrimidine-2,4 (1H, 3H)-diketone
As described in embodiment 1A, prepare title compound (0.3 g), with 1,3-difluoro isocyanato benzene, substitute the chloro-2-isocyanato of 1-benzene.MS(ESI +)m/z 323.1(M+H) +。
Embodiment 98B
The chloro-3-of 2-(2,6-difluorophenyl)-7-(methylthio group) Kui Linpyrimido quinoline [4,5-d] pyrimidine-4 (3H)-one
Preparation Example 98B as described in embodiment 1B (0.31 g), with embodiment 98A alternate embodiment 1A.MS(ESI +)m/z 341.2(M+H) +。
Embodiment 98C
3-(2,6-difluorophenyl)-2-(2,2-dimethoxy-ethyl is amino)-7-(methylthio group) Kui Linpyrimido quinoline [4,5-d] pyrimidine-4 (3H)-one
As described in embodiment 1C, prepare title compound (0.3 g), with embodiment 98B alternate embodiment 1B.MS(ESI +)m/z 409.4(M+H) +。
Embodiment 98D
4-(the fluoro-phenyl of 2,6-bis-)-8-methyl sulfenyl-4H-3,4,7,9,9b-pentaaza-cyclopenta [a] naphthalene-5-ketone
As described in embodiment 1D, prepare title compound (0.47g), with embodiment 98C alternate embodiment 1C.MS(ESI +)m/z 346.28(M+H) +。
Embodiment 98E
4-(the fluoro-phenyl of 2,6-bis-)-8-methylsulfinyl-4H-3,4,7,9,9b-pentaaza-cyclopenta [a] naphthalene-5-ketone
As described in embodiment 1E, prepare title compound (0.1g), with embodiment 98D alternate embodiment 1D.MS(ESI +)m/z 361.68(M+H) +。
Embodiment 98F
6-(2,6-difluorophenyl)-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 1F, prepare title compound (0.015g), with embodiment 98E alternate embodiment 1E.Use preparative HPLC purifying crude product (on Phenomenex Luna C8 (2) 5 μ m 100 AXIA posts (30mm * 75mm)).Use the gradient of acetonitrile (A) and 0.1% trifluoroacetic acid/water (B), flow velocity 50 mL/min (0-0.5 min, 10% A; 0.5-7.0 min linear gradient, 10-95% A; 7.0-10.0 min, 95% A; 10.0-12.0 min linear gradient, 95-10% A). 1H NMR(300 MHz, DMSO-d 6) δ 2.80-3.04(m, 5 H)3.07-3.29(m, 2 H)3.83(d, J=13.09 Hz, 4 H)7.12(d, J=1.59 Hz, 3 H)7.40(t, J=8.33 Hz, 2 H)7.56-7.83(m, 4 H)9.09(s, 1 H)9.57(s, 1 H)10.73(s, 1 H)。MS(ESI +)m/z 489.2(M+H) +。
Embodiment 99
6-(2-chloro-phenyl-)-2-{[2-(2-hydroxyethyl)-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 1F, prepare title compound, with 2-(7-amino-3,4-dihydro-isoquinoline-2 (1H)-yl) ethanol, substitute 4-(4-methylpiperazine-1-yl) aniline.Temperature of reaction is arranged on 100 ℃. 1H NMR(400 MHz, CD 3OD)δ 2.75(t, J=6.0 Hz, 2H), 2.97-2.84(m, 4H), 3.77(s, 2H), 3.81(t, J=6.0 Hz, 2H), 7.05(d, J=1.9 Hz, 1H), 7.48-7.13(m, 1H), 7.61-7.48(m, 5H), 7.71-7.65(m, 1H), 7.88-7.78(m, 1H), 9.13(s, 1H)。MS(ESI +)m/z 488.3(M+H) +。
Embodiment 100
6-(2-chloro-phenyl-)-2-{[3-(methylol)-4-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 100A
(2-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl)-5-nitrophenyl) methyl alcohol
By (the fluoro-5-nitrophenyl of 2-) methyl alcohol (4.500 g, 26.3 mmol), diisopropylethylamine (6.89 mL, 39.4 mmol) and 1-methyl isophthalic acid, the mixture of 4-Diazesuberane (4.25 mL, 34.2 mmol) in acetonitrile (150 mL) refluxes 24 hours.Evaporating solvent.By the saturated NaHCO of resistates 3the aqueous solution is processed, and extracts (twice) by ethyl acetate.By the organic layer MgSO of merging 4dry, filter.From organic layer, crystallization goes out title compound.
Embodiment 100B
(5-amino-2-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) phenyl) methyl alcohol
With in the flask of nitrogen purging, ethanol (30 mL) is joined in Pd/C (0.040 g, 0.038 mmol).Embodiment 100A (0.400 g, 1.508 mmol) is joined in said mixture.At H 2under atmosphere (use sacculus), this reaction is stirred 6 hours.By this reaction mixture of diatomite filtration, concentrated, title compound is provided.
Embodiment 100C
6-(2-chloro-phenyl-)-2-{[3-(methylol)-4-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 1F, prepare title compound, with embodiment 100B, substitute 4-(4-methylpiperazine-1-yl) aniline.Temperature of reaction is arranged at 100 ℃ 0.5 hour. 1H NMR(400 MHz, CD 3OD)δ 2.35-2.17(m, 2H), 3.00(s, 3H), 3.50-3.23(m, 6H), 3.64-3.54(m, 2H), 4.80(bs, 2H), 7.07(d, J=1.9 Hz, 1H), 7.33-7.23(m, 1H), 7.62-7.52(m, 3H), 7.72-7.63(m, 2H), 7.95-7.87(m, 1H), 8.16(bs, 1H), 9.14(s, 1H)。MS(ESI +)m/z 531.2(M+H) +。
Embodiment 101
6-(2-chloro-phenyl-)-2-{[4-(hexahydropyrrolo is [1,2-a] pyrazine-2 (1H)-yl also) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 1F, prepare title compound, with 4-(hexahydropyrrolo is [1,2-a] pyrazine-2 (1H)-yl also) aniline, substitute 4-(4-methylpiperazine-1-yl) aniline.Temperature of reaction is arranged at 100 ℃ 0.5 hour. 1H NMR(400 MHz, CD 3OD)δ 2.39-2.07(m, 4H), 3.18-2.89(m, 3H), 3.59-3.36(m, 4H), 3.86-3.69(m, 1H), 4.18-3.89(m, 1H), 7.12-7.03(m, 3H), 7.64-7.48(m, 3H), 7.74-7.65(m, 3H), 7.95-7.77(m, 1H), 9.09(bs, 1H)。MS(ESI +)m/z 513.3(M+H) +。
Embodiment 102
6-(2-chloro-phenyl-)-2-[(4-hydroxy-3-methyl phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 1F, prepare title compound, with 4-amino-2-cresols, substitute 4-(4-methylpiperazine-1-yl) aniline.Temperature of reaction is arranged at 100 ℃ 0.5 hour. 1H NMR(400 MHz, CD 3OD)δ 2.24(s, 3H), 6.84-6.76(m, 1H), 7.08(d, J=1.9 Hz, 1H), 7.48-7.28(m, 2H), 7.62-7.52(m, 4H), 7.79-7.65(m, 1H), 9.09(s, 1H)。MS(ESI +)m/z 419.3(M+H) +。
Embodiment 103
6-(2-chloro-phenyl-)-2-(4-[3-(diethylamino) propoxy-] and-3-aminomethyl phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
By embodiment 102 (0.050 g, 0.119 mmol), PPh 3(on polymer support) (3 mmol/g, 0.213 g), azoformic acid di-t-butyl ester (0.147 g) and 3-(diethylamino) third-1-alcohol (0.096 mL) mixture in tetrahydrofuran (THF) (2.5 mL) stirs 2 days.By ethyl acetate, dilute this reaction mixture, and pass through diatomite filtration.With HPLC, purify enriched material (referring to the scheme of embodiment 1F), the trifluoroacetate of title compound is provided. 1H NMR(500 MHz, CD 3OD)δ 1.40-1.34(m, 6H), 1.50-1.44(m, 2H), 2.31-2.22(m, 5H), 3.29-3.20(m, 2H), 3.44-3.37(m, 2H), 4.19-4.12(m, 2H), 7.01-6.93(m, 1H), 7.06(d, J=1.9 Hz, 1H), 7.61-7.49(m, 5H), 7.88-7.62(m, 2H), 9.11(s, 1H)。MS(ESI +)m/z 532.2(M+H) +。
Embodiment 104
6-(2-chloro-phenyl-)-2-{[3-methyl-4-(piperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
According to the described general method of embodiment 81, prepare title compound, by 4-(4-amino-2-methyl phenyl) piperazine-1-formic acid tertiary butyl ester, substitute 4-(5-aminopyridine-2-yl) piperazine-1-formic acid tertiary butyl ester. 1H NMR(500 MHz, CD 3OD)δ 2.39(s, 3H), 3.17-3.15(m, 4H), 3.46-3.36(m, 4H), 7.07(d, J=1.9 Hz, 1H), 7.21-7.12(m, 1H), 7.62-7.49(m, 4H), 7.92-7.64(m, 3H), 9.12(s, 1H)。MS(ESI +)m/z 487.2(M+H) +。
Embodiment 105
6-(2-chloro-phenyl-)-2-{[4-(Isosorbide-5-Nitrae-Diazesuberane-1-yl)-3-aminomethyl phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 105A
1-(2-methyl-4-nitrophenyl)-Isosorbide-5-Nitrae-Diazesuberane
As described in embodiment 100A, prepare title compound, with the fluoro-2-methyl-4-oil of mirbane of 1-and Isosorbide-5-Nitrae-Diazesuberane (having more 0.7 equivalent), substitute respectively (the fluoro-5-nitrophenyl of 2-) methyl alcohol and 1-methyl isophthalic acid, 4-Diazesuberane.
Embodiment 105B
4-(Isosorbide-5-Nitrae-Diazesuberane-1-yl)-3-monomethylaniline
As described in embodiment 100B, prepare title compound, with embodiment 105B alternate embodiment 100A.
Embodiment 105C
6-(2-chloro-phenyl-)-2-{[4-(Isosorbide-5-Nitrae-Diazesuberane-1-yl)-3-aminomethyl phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
By the mixture of embodiment 1E (0.075 g, 0.208 mmol), embodiment 105B (0.051 g, 0.250 mmol) and 4 trifluoroacetic acids (in acetonitrile (4.5 mL)) 70 ℃ of heated overnight.Concentrated this reaction mixture, purifies (referring to the scheme of embodiment 1F) with HPLC, and the trifluoroacetate of title compound is provided. 1H NMR(500 MHz, DMSO-d 6)δ 2.08-1.99(m, 2H), 2.32(s, 3H), 3.12-3.05(m, 2H), 3.30-3.25(m, 4H), 3.36-3.30(m, 2H), 7.08(d, J=1.8 Hz, 1H), 7.21-7.14(m, 1H), 7.65-7.52(m, 4H), 7.77-7.69(m, 2H), 8.78(bs, 2H), 9.10(s, 1H), 10.72-10.54(m, 1H)。MS(ESI +)m/z 501.2(M+H) +。
Embodiment 106
6-(2-chloro-phenyl-)-2-(2,3,4,5-tetrahydrochysene-1H-2-benzo-aza
Figure 187773DEST_PATH_IMAGE002
-7-base is amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 105C, prepare title compound, with 2,3,4,5-tetrahydrochysene-1H-benzo [c] azepine -7-amine alternate embodiment 105B. 1H NMR(400 MHz, CD 3OD)δ 2.09-2.01(m, 2H), 3.15-3.09(m, 2H), 3.53-3.47(m, 2H), 4.40(s, 2H), 7.08(d, J=1.9 Hz, 1H), 7.45-7.39(m, 1H), 7.62-7.53(m, 3H), 7.74-7.66(m, 2H), 7.87-7.77(m, 2H), 9.18(s, 1H)。MS(ESI +)m/z 458.2(M+H) +。
Embodiment 107
6-(2-chloro-phenyl-)-2-[(3-methyl-2,3,4,5-tetrahydrochysene-1H-3-benzo-aza
Figure 593663DEST_PATH_IMAGE002
-7-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 1F, prepare title compound, with 3-methyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine
Figure 443021DEST_PATH_IMAGE002
-7-amine substitutes 4-(4-methylpiperazine-1-yl) aniline.Temperature of reaction is arranged at 100 ℃ 0.5 hour. 1H NMR(400 MHz, DMSO-d 6)δ 2.88(d, J=4.5 Hz, 3H), 3.29-2.98(m, 6H), 3.69-3.60(m, 2H), 7.08(d, J=1.8 Hz, 1H), 7.31-7.24(m, 1H), 7.75-7.52(m, 7H), 7.79(s, 1H), 9.96(bs, 1H), 10.77(bs, 1H)。MS(ESI +)m/z 472.2(M+H) +。
Embodiment 108
6-(2-chloro-phenyl-)-2-[(1,1,2-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-7-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 1F, prepare title compound, with 1,1,2-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-7-amine substitutes 4-(4-methylpiperazine-1-yl) aniline.Temperature of reaction is arranged at 100 ℃ 0.5 hour. 1H NMR(400 MHz, CD 3OD)δ 1.77(s, 3H), 1.86(s, 3H), 3.01(s, 3H), 3.32-3.13(m, 2H), 3.83-3.51(m, 2H), 7.06(d, J=1.9 Hz, 1H), 7.30(t, J=11.8 Hz, 1H), 7.63-7.47(m, 3H), 7.72-7.65(m, 1H), 7.87-7.73(m, 3H), 9.18(s, 1H)。MS(ESI +)m/z 486.1(M+H) +。
Embodiment 109
6-(2,6-dichlorophenyl)-2-(2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-base amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 109A
7'-{[6-(2,6-dichlorophenyl)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino }-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-2'(3'H)-formic acid tertiary butyl ester
In embodiment 55d (1225 mg, 3.24 mmol) and metachloroperbenzoic acid (871 mg, 3.89 mmol), add 15 mL methylene dichloride.This reaction is stirred 15 minutes, adds 7'-amino-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-2'(3'H)-formic acid tertiary butyl ester (1066 mg, 3.89 mmol).This reaction is at room temperature stirred 25 minutes, with ethyl acetate dilution, use saturated NaHCO 3the aqueous solution, water and salt water washing, use MgSO 4dry, filter, concentrated.With Analogix 280 (SF 25-80 post), carry out chromatographic separation, use 10% to 60% ethyl acetate/hexane gradient elution 30 minutes, title compound is provided.MS(ESI +)m/z 604.2(M+H) +。
Embodiment 109B
6-(2,6-dichlorophenyl)-2-(2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-base amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
In the 3 mL dichloromethane solutions of embodiment 109A (0.12 g, 0.2 mmol), add excessive TFA.This reaction mixture is at room temperature stirred one hour.Concentrated this mixture, and by crude product high vacuum dry, provide title compound. 1H NMR(300 MHz, DMSO-d 6) δ 0.87-1.27(m, 4 H)3.18-3.38(m, 2 H)4.34-4.58(m, 2 H)6.94(d, J=8.48 Hz, 1 H)7.13(d, J=1.70 Hz, 1 H)7.39-8.01(m, 6 H)8.91-9.45(m, 3 H)10.88(s, 1 H)。MS(ESI +)m/z 504.2(M+H) +。
Embodiment 110
6-(2,6-dichlorophenyl)-2-{[3-methyl-4-(piperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 110A
4-(4-{[6-(2,6-dichlorophenyl)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino }-2-aminomethyl phenyl) piperazine-1-formic acid tertiary butyl ester
As described in embodiment 109A, prepare title compound (0.198 g), add diisopropylethylamine (0.103 g, 0.793 mmol), and substitute 7'-amino-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-2'(3'H by 4-(4-amino-2-methyl phenyl) piperazine-1-formic acid tertiary butyl ester)-formic acid tertiary butyl ester.With Analogix 280 (SF 12-24 post), carry out chromatographic separation, use 10% to 70% ethyl acetate/hexane gradient elution 30 minutes.MS(ESI +)m/z 621.0(M+H) +。
Embodiment 110B
6-(2,6-dichlorophenyl)-2-{[3-methyl-4-(piperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 109B, prepare title compound (0.015g), with embodiment 110A alternate embodiment 109A. 1H NMR(300 MHz, DMSO-d 6) δ 2.21-2.39(m, 3 H)2.96-3.11(m, J=4.76 Hz, 4 H)3.19-3.35(m, 4 H)7.05-7.22(m, 2 H)7.53-7.70(m, 2 H)7.70-7.86(m, 4 H)8.71(s, 2 H)9.14(s, 1 H)10.79(s, 1 H)。MS(ESI +)m/z 521.2(M+H) +。
Embodiment 111
6-(2,6-dichlorophenyl)-2-(1,2,3,4-tetrahydroisoquinoline-7-base is amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 111A
7-{[6-(2,6-dichlorophenyl)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino }-3,4-dihydro-isoquinoline-2 (1H)-formic acid tertiary butyl ester
As described in embodiment 109A, prepare title compound (0.11 g), add diisopropylethylamine (0.103 g, 0.793 mmol), and with 7-amino-3,4-dihydro-isoquinoline-2 (1H)-formic acid tertiary butyl ester substitutes 7'-amino-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-2'(3'H)-formic acid tertiary butyl ester.With Analogix 280 (SF 12-24 post), carry out chromatographic separation, use 10% to 60% ethyl acetate/hexane gradient elution 30 minutes.MS(ESI +)m/z 578.3(M+H) +。
Embodiment 111B
6-(2,6-dichlorophenyl)-2-{[3-methyl-4-(piperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 109B, prepare title compound (0.015g), with embodiment 111A alternate embodiment 109A. 1H NMR(300 MHz, DMSO-d 6) δ 2.90-3.08(m, 2 H)3.32-3.52(m, 2 H)4.36(s, 2 H)7.13(d, J=1.59 Hz, 1 H)7.29(d, J=8.73 Hz, 1 H)7.57-7.73(m, 3 H)7.73-7.80(m, 2 H)7.85(s, 1 H)9.00(s, 2 H)9.18(s, 1 H)10.90(s, 1 H)。MS(ESI +)m/z 478.2(M+H) +。
Embodiment 112
6-(2-chloro-phenyl-)-2-{[3-ethyl-4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 112A
1-methyl-4-(4-nitro-2-ethenylphenyl) piperazine
By 1-(the bromo-4-nitrophenyl of 2-)-4-methylpiperazine (0.900 g, 3.00 mmol), tetrakis triphenylphosphine palladium (0) (0.104 g, 0.090 mmol) and tributyl (vinyl) tin (0.964 mL, 3.30 mmol) 1, mixture in 4-diox (30 mL) is degassed, and 105 ℃ of heated overnight.After cooling, filter this suspension, concentrated, purifying on 40 g posts, is used ISCO Companion flash chromatographic system, with methanol/ethyl acetate (5:95 to 10:90) wash-out, provides title compound.
Embodiment 112B
3-ethyl-4-(4-methylpiperazine-1-yl) aniline
In 50 ml pressure bottles, embodiment 112A (0.558 g) (in ethanol (20 mL) and tetrahydrofuran (THF) (5 mL)) is joined in 5% Pd-C (moistening) catalyzer, and in the atmosphere of hydrogen of 30 psi, at room temperature stir 16 hours.By this reaction mixture of diatomite filtration, concentrated, title compound is provided.
Embodiment 112C
6-(2-chloro-phenyl-)-2-{[3-ethyl-4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 1F, prepare title compound, with embodiment 112B, substitute 4-(4-methylpiperazine-1-yl) aniline.Temperature of reaction is arranged at 100 ℃ 0.5 hour. 1H NMR(400 MHz, CD 3OD)δ 1.35-1.27(m, 3H), 2.85-2.75(m, 2H), 2.99(s, 3H), 3.25-3.10(m, 4H), 3.38-3.34(m, 2H), 3.64-3.56(m, 2H), 7.06(d, J=1.9 Hz, 1H), 7.23(d, J=7.1 Hz, 1H), 7.62-7.52(m, 3H), 7.87-7.63(m, 4H), 9.12(s, 1H)。MS(ESI +)m/z 515.3(M+H) +。
Embodiment 113
6-(2-chloro-phenyl-)-2-{[2-(cyclohexyl methyl)-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 113A
2-(cyclohexyl methyl)-4,4-dimethyl-7-nitro-1,2,3,4-tetrahydroisoquinoline
By sodium cyanoborohydride (0.600 g, 9.55 mmol) join 4,4-dimethyl-7-nitro-1,2,3,4-tetrahydroisoquinoline (0.600 g, 2.91 mmol), acetic acid (0.210 mL, 3.66 mmol) and in methyl alcohol (40 mL) solution of hexahydrobenzaldehyde (0.4 g, 3.57 mmol).This reaction mixture is stirred 16 hours at 35 ℃.With saturated sodium bicarbonate solution, neutralize this reaction, and by this mixture concentrating under reduced pressure.Dilute with water resistates, and extract by ethyl acetate (3 x 50 mL).The organic layer merging with salt water washing, uses Na 2sO 4dry, filter, concentrated.With silica gel chromatography crude product (3% ethyl acetate/petroleum ether), provide title compound.
Embodiment 113B
2-(cyclohexyl methyl)-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-amine
Embodiment 113A (0.7g, 2.315 mmol) is joined in Pd/C (10%, 0.1 g, 0.094 mmol)/methyl alcohol (50 mL).This mixture is degassed, and use hydrogen purge.In atmosphere of hydrogen, stir this reaction mixture 5 hours.With silica gel chromatography crude product (50:1 CH 2cl 2/ methyl alcohol), provide title compound.LC-MS: m/e=273(M+H) +。 1H NMR(400 MHz, CDCl 3), δ 7.08(d, J=8.4 Hz, 1 H), 6.53(dd, J=8.4 Hz, 2.4 Hz, 1 H), 6.33(d, J=2.0 Hz, 1 H), 3.49(br, 2 H), 3.44(s, 2 H), 2.32(s, 2 H), 2.20(d, J=7.2 Hz, 2 H), 1.84(d, J=12.8 Hz, 2 H), 1.66-1.72(m, 3 H), 1.53-1.60(m, 1 H), 1.24(s, 6 H), 1.15-1.28(m, 2 H), 0.83-0.92(m, 2 H)。
Embodiment 113C
6-(2-chloro-phenyl-)-2-{[2-(cyclohexyl methyl)-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 1E (0.065 g, 0.181 mmol), embodiment 113B (0.059 g, 0.217 mmol) and the mixture of trifluoroacetic acid (0.028 mL, 0.361 mmol) in acetonitrile (3 mL) are heated 1 hour at 70 ℃.Concentrated this reaction mixture, purifies (referring to the scheme of embodiment 1F) with HPLC, and the trifluoroacetate of title compound is provided. 1H NMR(400 MHz, CD 3OD)δ 1.36-1.04(m, 3H), 1.54-1.35(m, 8H), 1.87-1.71(m, 5H), 2.12-2.04(m, 1H), 3.26-3.18(m, 3H), 3.73-3.58(m, 1H), 4.60-4.42(m, 2H), 7.06(d, J=1.8 Hz, 1H), 7.62-7.53(m, 4H), 7.78-7.62(m, 3H), 7.88(d, J=1.9 Hz, 1H), 9.17(s, 1H)。MS(ESI +)m/z 568.3(M+H) +。
Embodiment 114
6-(2,6-dichlorophenyl)-2-{[2-(dimethylamino)-2,3-dihydro-1H-indenes-5-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 109A, prepare title compound (0.045 g), add diisopropylethylamine (0.098 g, 0.53 mmol), and use N 2, N 2-dimethyl-2,3-dihydro-1H-indenes-2,5-diamines substitutes 7'-amino-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-2'(3'H)-formic acid tertiary butyl ester.Use preparative HPLC to carry out purifying (on Phenomenex Luna C8 (2) 5 μ um 100 AXIA posts (30mm * 75mm)).Use the gradient of acetonitrile (A) and 0.1% trifluoroacetic acid/water (B), flow velocity 50 mL/min (0-0.5 min, 10% A; 0.5-7.0 min linear gradient, 10-95% A; 7.0-10.0 min, 95% A; 10.0-12.0 min linear gradient, 95-10% A). 1H NMR(300 MHz, DMSO-d 6) δ 2.85(d, J=4.41 Hz, 6 H)3.00-3.48(m, 4 H)4.13(dd, J=14.75, 7.29 Hz, 1 H)7.00-7.21(m, 1 H)7.20-7.43(m, 1 H)7.45-7.99(m, 6 H)9.16(s, 1 H)9.83(s, 1 H)10.86(s, 1 H)。MS(ESI +)m/z 506.2(M+H) +。
Embodiment 115
6-(2,6-dichlorophenyl)-2-(4-[4-(third-2-yl) piperazine-1-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 109A, prepare title compound (0.09 g), add diisopropylethylamine (0.103 g, 0.79 mmol), and substitute 7'-amino-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-2'(3'H with 4-(4-sec.-propyl piperazine-1-yl) aniline)-formic acid tertiary butyl ester.Crude product is ground together with ethyl acetate, title compound is provided. 1H NMR(300 MHz, DMSO-d 6) δ 1.01(d, J=6.44 Hz, 6 H)2.54-2.66(m, 5 H)3.12(s, 4 H)7.63(d, J=2.03 Hz, 1 H)7.65(s, 1 H)7.74(s, 5 H)7.76(s, 1 H)7.83(s, 1 H)9.09(s, 1 H)10.70(s, 1 H)。MS(ESI +)m/z 549.2(M+H) +。
Embodiment 116
6-(2,6-dichlorophenyl)-2-{[4-(hexahydropyrrolo is [1,2-a] pyrazine-2 (1H)-yl also) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 109A, prepare title compound, add diisopropylethylamine (0.103 g, 0.79 mmol), and with 4-(hexahydropyrrolo also [1,2-a] pyrazine-2 (1H)-yl) the alternative 7'-amino-1'H-spiral shell of aniline [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-2'(3'H)-formic acid tertiary butyl ester.Crude product is ground together with ethyl acetate, title compound is provided. 1H NMR(300 MHz, DMSO-d 6) δ 1.38(dd, J=10.91, 6.94 Hz, 1 H)1.54-1.95(m, 3 H)1.97-2.17(m, 2 H)2.16-2.34(m, 1 H)2.41(t, J=10.51 Hz, 1 H)2.66-2.83(m, 1 H)2.97-3.13(m, 2 H)3.70(dd, J=44.81, 11.10 Hz, 2 H)7.02(d, J=8.33 Hz, 2 H)7.10(d, J=1.59 Hz, 1 H)7.43-7.95(m, 6 H)9.10(s, 1 H)10.70(s, 1 H)。MS(ESI +)m/z 547.3(M+H) +。
Embodiment 117
6-(2-chloro-phenyl-)-2-{[2-(2-ethyl-butyl)-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 117A
2-(2-ethyl-butyl)-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-amine
As described in embodiment 113A and embodiment 113B, prepare title compound, with 2-ethyl butyraldehyde, substitute hexahydrobenzaldehyde.LC-MS: m/e=261(M+H) +。 1H NMR(400 MHz, CDCl 3), δ 7.08(d, J=8.4 Hz, 1 H), 6.53(dd, J=8.4 Hz, 2.4 Hz, 1 H), 6.32(d, J=2.4 Hz, 1 H), 3.48(br, 2 H), 3.44(s, 2 H), 2.33(s, 2 H), 2.24(d, J=7.6 Hz, 2 H), 1.50-1.53(m, 1 H), 1.31-1.44(m, 4 H), 1.25(s, 6 H), 0.87(t, J=7.4 Hz, 6 H)。
Embodiment 117B
6-(2-chloro-phenyl-)-2-{[2-(2-ethyl-butyl)-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 113C, prepare title compound, with embodiment 117A alternate embodiment 113B. 1H NMR(500 MHz, CD 3OD)δ 1.01(t, J=7.4 Hz, 6H), 1.69-1.37(m, 10H), 2.04-1.99(m, 1H), 3.29(s, 3H), 3.68-3.56(m, 1H), 4.67-4.49(m, 2H), 7.05(d, J=1.9 Hz, 1H), 7.62-7.52(m, 4H), 7.77-7.66(m, 2H), 7.87(d, J=1.9 Hz, 1H), 9.16(s, 1H)。MS(ESI +)m/z 556.3(M+H) +。
Embodiment 118
6-(2,6-dichlorophenyl)-2-(4-[2-(4-methylpiperazine-1-yl) ethyl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
In embodiment 55D (75 mg, 0.198 mmol) and metachloroperbenzoic acid (51.1 mg, 0.228 mmol), add 2 mL methylene dichloride.This reaction is stirred 15 minutes, and concentrated.Crude product is dissolved in 2 mL acetonitriles, then adds 4-(2-(4-methylpiperazine-1-yl) ethyl) aniline (50.0 mg, 0.228 mmol) and trifluoroacetic acid (45 mg, 0.4 mmol).This reaction is heated to 50 ℃, keeps 1.5 hours, be then cooled to ambient temperature overnight.By ethyl acetate, dilute this reaction, use saturated NaHCO 3the aqueous solution, water and salt water washing, use MgSO 4dry, filter, concentrated.Crude product is dissolved in methyl alcohol, and processes with 2M HCl/ diethyl ether.Stir this mixture, until start to form solid, then with ether, dilute.Stir this mixture 10 minutes, filter, title compound is provided. 1H NMR(300 MHz, DMSO-d 6) δ 2.84(s, 3 H)3.05(s, 2 H)3.22-3.52(m, 6 H)3.59-3.75(m, 4 H)7.12(d, J=2.03 Hz, 1 H)7.34(d, J=8.48 Hz, 2 H)7.47-8.12(m, 6 H)9.17(s, 1 H)10.86(s, 1 H)11.61(s, 1 H)。MS(ESI +)m/z 549.3(M+H) +。
Embodiment 119
6-(2,6-dichlorophenyl)-2-(1-[2-(dimethylamino) ethyl] and-2,3-dihydro-1H-indoles-5-yl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
In embodiment 55D (70.0 mg, 0.185 mmol) and metachloroperbenzoic acid (47.7 mg, 0.213 mmol), add CH 2cl 2(2 mL).This reaction is stirred 15 minutes.Evaporating solvent.Resistates is dissolved in acetonitrile (2.000 mL), with 1-(2-(dimethylamino) ethyl) indoline-5-amine (43.7 mg, 0.213 mmol), processes, then use trifluoroacetic acid (0.029 mL, 0.370 mmol) to process.This mixture is heated 2 hours at 60 ℃.Evaporate most solvents.The mixture obtaining is diluted by ethyl acetate, use saturated NaHCO 3the aqueous solution, water and salt water washing.By the organic layer MgSO of merging 4dry, filter, concentrated, with HPLC, purify (referring to the scheme of embodiment 1F), the trifluoroacetate of title compound is provided. 1H NMR(400 MHz, CD 3OD)δ 2.98(d, J=5.7 Hz, 6H), 3.14-3.02(m, 2H), 3.72-3.37(m, 6H), 6.81-6.70(m, 1H), 7.06(d, J=1.8 Hz, 1H), 7.61-7.44(m, 3H), 7.70-7.61(m, 2H), 7.89-7.74(m, 1H), 9.09(s, 1H)。MS(ESI +)m/z 535.2(M+H) +。
Embodiment 120
6-(2,6-dichlorophenyl)-2-{[3-ethyl-4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 119, prepare title compound, with embodiment 112B, substitute 1-(2-(dimethylamino) ethyl) indoline-5-amine. 1H NMR(400 MHz, CD 3OD)δ 1.35-1.22(m, 3H), 2.86-2.69(m, 2H), 3.00(s, 3H), 3.38-3.10(m, 6H), 3.64-3.56(m, 2H), 7.08(d, J=1.8 Hz, 1H), 7.27-7.12(m, 1H), 7.57(dd, J=9.1, 7.0 Hz, 1H), 7.94-7.63(m, 5H), 9.15(bs, 1H)。MS(ESI +)m/z 549.2(M+H) +。
Embodiment 121
6-(2,6-dichlorophenyl)-2-{[3-(methylol)-4-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 119, prepare title compound, with embodiment 100B, substitute 1-(2-(dimethylamino) ethyl) indoline-5-amine. 1H NMR(400 MHz, CD 3OD)δ 2.26-2.10(m, 2H), 3.01(s, 3H), 3.26-3.19(m, 2H), 3.68-3.33(m, 6H), 4.80-4.77(m, 2H), 7.08(d, J=1.9 Hz, 1H), 7.33-7.26(m, 1H), 7.58(dd, J=9.1, 7.0 Hz, 1H), 7.70-7.63(m, 3H), 7.94(d, J=1.9 Hz, 1H), 8.20(bs, 1H), 9.17(s, 1H)。MS(ESI +)m/z 565.2(M+H) +。
Embodiment 122
6-(2,6-dichlorophenyl)-2-(1,2,3,4-tetrahydroisoquinoline-6-base is amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 109A, prepare title compound (0.068 g), amino-3 with 6-, 4-dihydro-isoquinoline-2 (1H)-formic acid tertiary butyl ester substitutes 7'-amino-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-2'(3'H)-formic acid tertiary butyl ester.Crude product is dissolved in a small amount of methylene dichloride, and processes 1 hour with TFA.Except desolventizing, and compound is absorbed in a small amount of methyl alcohol, with excessive 2N HCl/ diethyl ether, processes 1 hour.This suspension is diluted with 50 mL diethyl ether, and cross filter solid, dry. 1H NMR(300 MHz, DMSO-d 6) δ 2.98-3.16(m, 2 H)3.28-3.48(m, 2 H)4.18-4.31(m, 2 H)7.13(d, J=1.70 Hz, 1 H)7.20-7.32(m, 1 H)7.54-7.87(m, 6 H)9.18(s, 1 H)9.25(s, 3 H)10.88(s, 1 H)。MS(ESI +)m/z 478.29(M+H) +。
Embodiment 123
6-(the chloro-4-fluorophenyl of 2,6-bis-)-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 123A
4-(the chloro-4-fluorophenyl of 2,6-bis-)-8-methyl sulfenyl-4H-3,4,7,9,9b-pentaaza-cyclopenta [a] naphthalene-5-ketone
According to the described general method of embodiment 1A to embodiment 1D, prepare title compound, in embodiment 1A, with the fluoro-2-isocyanato of the chloro-5-of 1,3-bis-benzene, substitute the chloro-2-isocyanato of 1-benzene, and reduce the reaction times (2 hours).With ordinary skill, revise reactant aftertreatment and purification process.The change of embodiment 1A: during aftertreatment, by water layer acidifying, and be settled out product.The change of embodiment 1B: purification of target product on silica column, use ISCO Companion flash chromatographic system, use CH 2cl 2/ hexane (90:10 to 95:5) wash-out.The change of embodiment 1D: grind together with ethyl acetate, separate targets product, then uses NaHCO 3solution washing.
Embodiment 123B
6-(the chloro-4-fluorophenyl of 2,6-bis-)-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
In embodiment 123A (60.0 mg, 0.151 mmol) and metachloroperbenzoic acid (40.7 mg, 0.182 mmol), add 1,2-ethylene dichloride (2 mL).This reaction mixture is stirred 15 minutes.With 4-(4-methylpiperazine-1-yl) aniline (34.8 mg, 0.182 mmol) and trifluoroacetic acid (0.023 mL, 0.303 mmol), process this mixture, and be heated to 60 ℃, keep 1.5 hours.Concentrated this reaction mixture, purifies (referring to the scheme of embodiment 1F) with HPLC, and the trifluoroacetate of title compound is provided. 1H NMR(400 MHz, CD 3OD)δ 2.98(s, 3H), 3.15-3.02(m, 2H), 3.40-3.21(m, 2H), 3.63(d, J=11.2 Hz, 2H), 3.86(d, J=12.5 Hz, 2H), 7.12-7.05(m, 3H), 7.57(d, J=8.2 Hz, 2H), 7.90-7.67(m, 3H), 9.11(s, 1H)。MS(ESI +)m/z 539.2(M+H) +。
Embodiment 124
6-(the chloro-4-fluorophenyl of 2,6-bis-)-2-{[3-methyl-4-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 123B, prepare title compound, with 3-methyl-4-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) aniline, substitute 4-(4-methylpiperazine-1-yl) aniline.Carry out aqueous solution processing, then carry out HPLC. 1H NMR(400 MHz, CD 3OD)δ 2.28-2.14(m, 2H), 2.45-2.37(m, 2H), 2.65(s, 3H), 3.01(s, 3H), 3.25-3.17(m, 2H), 3.74-3.32(m, 4H), 7.09(d, J=1.8 Hz, 1H), 7.21(bs, 1H), 7.99-7.50(m, 5H), 9.14(s, 1H)。MS(ESI +)m/z 567.2(M+H) +。
Embodiment 125
6-(the chloro-4-fluorophenyl of 2,6-bis-)-2-[(2'-methyl-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 123B, prepare title compound, with 2'-methyl-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9] alternative 4-(4-methylpiperazine-1-yl) aniline of-7'-amine.Carry out aqueous solution processing, then carry out HPLC purifying. 1H NMR(400 MHz, CD 3OD)δ 1.48-1.08(m, 4H), 3.09(s, 3H), 3.35-3.22(m, 1H), 3.67(d, J=12.6 Hz, 1H), 4.76-4.52(m, 2H), 6.96(d, J=8.3 Hz, 1H), 7.10(d, J=1.8 Hz, 1H), 7.57(d, J=8.1 Hz, 2H), 7.76-7.62(m, 2H), 7.89(d, J=1.7 Hz, 1H), 9.18(s, 1H)。MS(ESI +)m/z 536.1(M+H) +。
Embodiment 126
6-(the chloro-4-fluorophenyl of 2,6-bis-)-2-{[2-(dimethylamino)-2,3-dihydro-1H-indenes-5-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 123B, prepare title compound, use N 2, N 2-dimethyl-2,3-dihydro-1H-indenes-2,5-diamines substitutes 4-(4-methylpiperazine-1-yl) aniline.Carry out aqueous solution processing, then carry out HPLC purifying. 1H NMR(400 MHz, CD 3OD)δ 2.96(s, 6H), 3.26-3.16(m, 2H), 3.56-3.41(m, 2H), 4.22-4.13(m, 1H), 7.09(d, J=1.9 Hz, 1H), 7.36-7.30(m, 1H), 7.68-7.50(m, 3H), 7.90-7.78(m, 2H), 9.15(s, 1H)。
Embodiment 127
6-(2,6-dichlorophenyl)-2-(4-[(4-methylpiperazine-1-yl) and methyl] phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
In embodiment 55D (75 mg, 0.198 mmol) and metachloroperbenzoic acid (53.3 mg, 0.238 mmol), add 2 mL methylene dichloride.This reaction is stirred 15 minutes, add during this period 4-((4-methylpiperazine-1-yl) methyl) aniline (48.9 mg, 0.238 mmol), then add trifluoroacetic acid (0.031 mL, 0.397 mmol).This mixture is stirred 1 hour at 50 ℃, at room temperature stir and spend the night.By ethyl acetate, dilute this mixture, use saturated NaHCO 3the aqueous solution, water and salt water washing, use MgSO 4dry, filter, concentrated.Crude product is dissolved in methyl alcohol, and processes 1 hour with 2N HCl/ diethyl ether.This mixture is diluted with diethyl ether, and filter.Solid is ground together with 1:1 DMSO/ methanol solution, with ethyl acetate dilution, filter, high vacuum dry, provides title compound. 1H NMR(501 MHz, DMSO-d 6) δ 2.53(s, 2 H)2.78(s, 2 H)3.15(s, 3 H)3.19-3.50(m, 4 H)3.91(s, 2 H)7.09(d, J=1.18 Hz, 1 H)7.47(d, J=7.58 Hz, 2 H)7.55-7.64(m, 1 H)7.66-7.74(m, 2 H)7.80(d, J=1.66 Hz, 1 H)7.86(d, J=8.06 Hz, 2 H)9.16(s, 1 H)。MS(ESI +)m/z 534.9(M+H) +。
Embodiment 128
6-(2,6-dichlorophenyl)-2-(4-[(3R, 5S) and-3,5-lupetazin-1-yl]-3-fluorophenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 109A, prepare title compound (0.09 g), with 4-((3S, 5R)-3,5-lupetazin-1-yl) the alternative 7'-amino-1'H-spiral shell of-3-fluoroaniline [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-2'(3'H)-formic acid tertiary butyl ester.Final compound is dissolved in 2 mL methyl alcohol, with excessive 2M HCl/ diethyl ether, processes 1 hour.Filter solid matter, high vacuum dry, provides the HCL salt of title compound. 1H NMR(300 MHz, DMSO-d 6) δ 1.20-1.41(m, 6 H)2.63-2.90(m, 2 H)3.35-3.55(m, 4 H)7.06-7.30(m, 2 H)7.51-7.85(m, 6 H)8.71(s, 1 H)9.18(s, 1 H)9.32(s, 1 H)10.91(s, 1 H)。MS(ESI +)m/z 552.5.0(M+H) +。
Embodiment 129
6-(2,6-dichlorophenyl)-2-{[3, the fluoro-4-of 5-bis-(piperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 129A
4-(4-{[6-(2,6-dichlorophenyl)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino }-2,6-difluorophenyl) piperazine-1-formic acid tertiary butyl ester
As described in embodiment 109A, prepare title compound (0.039 g), with 4-, (4-amino-2,6-difluorophenyl) piperazine-1-formic acid tertiary butyl ester substitutes 7'-amino-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-2'(3'H)-formic acid tertiary butyl ester.Crude product reaction mixture is ground together with ethyl acetate, title compound is provided.MS(ESI+)m/z 642.93(M+H)+。
Embodiment 129B
6-(2,6-dichlorophenyl)-2-{[3, the fluoro-4-of 5-bis-(piperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 109B, prepare title compound (0.03g), with embodiment 129A alternate embodiment 109A.Tfa salt is dissolved in methyl alcohol, with excessive 2M HCl/ diethyl ether, processes, stir, until start to form solid.With ether, dilute this mixture, stir 10 minutes, then cross filter solid, title compound is provided. 1H NMR(300 MHz, DMSO-d 6) δ 3.21(d, 4 H)3.29(d, 4 H)7.15(d, J=1.59 Hz, 1 H)7.49-7.72(m, 3 H)7.71-7.90(m, 3 H)8.77(s, 2 H)9.24(s, 1 H)11.06(s, 1 H)。MS(ESI +)m/z 543.2(M+H) +。
Embodiment 130
6-(2-chloro-phenyl-)-2-{[2-(cyclopropyl methyl)-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 130A
2-(cyclopropyl methyl)-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-amine
As described in embodiment 113A and embodiment 113B, prepare title compound, with cyclopropyl formaldehyde, substitute hexahydrobenzaldehyde.LC-MS: m/e=231(M+H) +。 1H NMR(400 MHz, CDCl 3), δ 7.09(d, J=8.4 Hz, 1 H), 6.54(dd, J=8.0 Hz, 2.4 Hz, 1 H), 6.35(d, J=2.4 Hz, 1 H), 3.55(br, 2 H), 3.49(s, 2 H), 2.46(s, 2 H), 2.35(d, J=2.4 Hz, 2 H), 1.26(s, 6 H), 0.88-1.00(m, 1 H), 0.51-0.56(m, 2 H), 0.15-0.18(m, 2 H)。
Embodiment 130B
6-(2-chloro-phenyl-)-2-{[2-(cyclopropyl methyl)-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
By embodiment 1E (65.0 mg, 0.181 mmol), embodiment 130A (49.9 mg, 0.217 mmol) and 2,2, the mixture of 2-trifluoroacetic acid (0.028 mL, 0.361 mmol) in acetonitrile (2 mL) heats 1.5 hours at 60 ℃.Concentrated this mixture, and surplus solution is diluted by ethyl acetate, saturated NaHCO used 3the aqueous solution, salt solution and water washing, use MgSO 4dry, filter, concentrated, with HPLC, purify (referring to the scheme of embodiment 1F), the trifluoroacetate of title compound is provided. 1H NMR(500 MHz, CD 3OD)δ 0.54(d, J=4.2 Hz, 2H), 0.86(s, 2H), 1.34-1.23(m, 1H), 1.49(s, 3H), 1.53(s, 3H), 3.44-3.11(m, 2H), 3.76-3.66(m, 1H), 4.68-4.44(m, 2H), 7.06(d, J=1.6 Hz, 1H), 7.63-7.44(m, 4H), 7.82-7.63(m, 3H), 7.88(s, 1H), 9.17(s, 1H)。MS(ESI +)m/z 526.2(M+H) +。
Embodiment 131
6-(2-chloro-phenyl-)-2-{[4,4-dimethyl-2-(pyridin-3-yl methyl)-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 131A
4,4-dimethyl-2-(pyridin-3-yl methyl)-1,2,3,4-tetrahydroisoquinoline-7-amine
As described in embodiment 113A and embodiment 113B, prepare title compound, in embodiment 113A, with 2-(pyridin-3-yl) acetaldehyde, substitute hexahydrobenzaldehyde (T=10 ℃).LC-MS: m/e=268(M+H) +。 1H NMR(400 MHz, CDCl 3)δ 8.53(s, 1 H), 8.45(dd, J=4.6 Hz, 1.0 Hz, 1 H), 7.69(d, J=7.6 Hz, 1 H), 7.17-7.20(m, 1 H), 7.02(d, J=8.4 Hz, 1 H), 6.48(dd, J=8.4 Hz, 2.4 Hz, 1 H), 6.22(d, J=2.4 Hz, 1 H), 3.56(s, 2 H), 3.46(s, 2 H), 2.31(s, 2 H), 1.16(s, 6 H)。
Embodiment 131B
6-(2-chloro-phenyl-)-2-{[4,4-dimethyl-2-(pyridin-3-yl methyl)-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 130B, prepare title compound, with embodiment 131A alternate embodiment 130A. 1H NMR(500 MHz, CD 3OD)δ 1.43(s, 6H), 3.36-3.35(m, 2H), 4.45(s, 2H), 4.61(s, 2H), 7.07(d, J=1.8 Hz, 1H), 7.62-7.47(m, 4H), 7.97-7.64(m, 5H), 8.33-8.26(m, 1H), 8.81-8.76(m, 1H), 8.88(bs, 1H), 9.17(s, 1H)。MS(ESI +)m/z 563.1(M+H) +。
Embodiment 132
6-(2-chloro-phenyl-)-2-{[4,4-dimethyl-2-(thiene-3-yl-methyl)-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 132A
4,4-dimethyl-2-(thiene-3-yl-methyl)-1,2,3,4-tetrahydroisoquinoline-7-amine
As described in embodiment 113A and embodiment 113B, prepare title compound, with thiophene-3-formaldehyde, substitute hexahydrobenzaldehyde.LC-MS: m/e=273(M+H) +。 1H NMR(400 MHz, CDCl 3), δ 7.26-7.28(m, 1 H), 7.17(s, 1 H), 7.12(d, J=5.2 Hz, 1 H), 7.09(d, J=8.4 Hz, 1 H), 6.54(dd, J=8.4 Hz, 2.4 Hz, 1 H), 6.31(d, J=2.4 Hz, 1 H), 3.64(s, 2 H), 3.52(s, 2 H), 3.50(br, 2 H), 2.37(s, 2 H), 1.23(s, 6 H)。
Embodiment 132B
6-(2-chloro-phenyl-)-2-{[4,4-dimethyl-2-(thiene-3-yl-methyl)-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 130B, prepare title compound, with embodiment 132A alternate embodiment 130A. 1H NMR(500 MHz, CD 3OD)δ 1.44(s, 6H), 3.48-3.30(m, 2H), 4.62-4.39(m, 4H), 7.06(s, 1H), 7.34(d, J=5.0 Hz, 1H), 7.63-7.51(m, 4H), 7.87-7.63(m, 6H), 9.17(s, 1H). . MS(ESI +)m/z 568.2(M+H) +。
Embodiment 133
6-(2-chloro-phenyl-)-2-[(1,1,2-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-6-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 130B, prepare title compound, with 1,1,2-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-6-amine alternate embodiment 130A. 1H NMR(500 MHz, CD 3OD)δ 1.75(s, 3H), 1.85(s, 3H), 3.01(s, 3H), 3.36-3.17(m, 2H), 3.78-3.58(m, 2H), 7.07(d, J=1.9 Hz, 1H), 7.62-7.46(m, 4H), 7.88-7.66(m, 4H), 9.17(s, 1H). . MS(ESI +)m/z 486.2(M+H) +。
Embodiment 134
6-(2,6-dichlorophenyl)-2-{[4-(pyrrolidin-2-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 134A
2-(4-{[6-(2,6-dichlorophenyl)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } phenyl) tetramethyleneimine-1-formic acid tertiary butyl ester
As described in embodiment 109A, prepare title compound (0.012 g), the alternative 7'-amino-1'H-spiral shell of use 2-(4-aminophenyl) tetramethyleneimine-1-formic acid tertiary butyl ester [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-2'(3'H)-formic acid tertiary butyl ester.MS(ESI+)m/z 591.93(M+H)+。
Embodiment 134B
6-(2,6-dichlorophenyl)-2-{[4-(pyrrolidin-2-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 109B, prepare title compound (0.01g), with embodiment 134A alternate embodiment 109A.Tfa salt is dissolved in methyl alcohol, with excessive 2M HCl/ diethyl ether, processes, stir, until start to form solid.With ether, dilute this mixture, stir 10 minutes, filter, obtain title compound. 1H NMR(300 MHz, DMSO-d 6) δ 1.88-2.21(m, 3 H)2.23-2.46(m, 1 H)3.18-3.43(m, 2 H)4.55(s, 1 H)7.14(d, J=1.98 Hz, 2 H)7.42-7.71(m, 3 H)7.70-7.82(m, 2 H)7.90(s, 2 H)8.56-9.09(m, 1 H)9.20(s, 1 H)9.93(s, 1 H)10.98(s, 1 H)。MS(ESI +)m/z 429.2(M+H) +。
Embodiment 135
6-(2,6-dichlorophenyl)-2-{[4-(piperidin-2-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 135A
2-(4-{[6-(2,6-dichlorophenyl)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } phenyl) piperidines-1-formic acid tertiary butyl ester
As described in embodiment 109A, prepare title compound (0.012 g), the alternative 7'-amino-1'H-spiral shell of use 2-(4-aminophenyl) piperidines-1-formic acid tertiary butyl ester [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-2'(3'H)-formic acid tertiary butyl ester.MS(ESI +)m/z 605.98(M+H) +。
Embodiment 135B
6-(2,6-dichlorophenyl)-2-{[4-(piperidin-2-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 109B, prepare title compound (0.095g), with embodiment 135A alternate embodiment 109A.Tfa salt is dissolved in methyl alcohol, with excessive 2M HCl/ diethyl ether, processes, stir, until start to form solid.With ether, dilute this mixture, stir 10 minutes, filter, title compound is provided. 1H NMR(300 MHz, DMSO-d 6) δ 1.90(d, J=15.47 Hz, 6 H)2.95-3.19(m, 1 H)3.24-3.45(m, J=7.01 Hz, 1 H)4.22(s, 1 H)7.14(d, J=1.98 Hz, 1 H)7.50-7.70(m, 3 H)7.71-7.81(m, 2 H)7.90(d, J=7.93 Hz, 3 H)8.98(s, 2 H)9.20(s, 1 H)10.97(s, 1 H)。MS(ESI +)m/z 506.2(M+H) +。
Embodiment 136
The chloro-4-of 2-{[3-(4-methylpiperazine-1-yl) phenyl] amino }-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 127, prepare title compound (0.075 g), with the chloro-4-of 3-(4-methylpiperazine-1-yl) aniline, substitute 4-((4-methylpiperazine-1-yl) methyl) aniline.Crude product is ground together with ethyl acetate, title compound is provided. 1H NMR(300 MHz, DMSO-d 6) δ 2.23(d, 4 H)2.97(d, 4 H)7.13(d, J=1.36 Hz, 1 H)7.24(d, J=8.82 Hz, 1 H)7.56-7.69(m, 1 H)7.71-7.83(m, 3 H)7.88(d, J=2.37 Hz, 1 H)9.04-9.27(m, 1 H)10.66-11.05(m, 1 H)。MS(ESI +)m/z 555.2(M+H) +。
Embodiment 137
6-(2,6-dichlorophenyl)-2-(3-methoxyl group-4-[4-(third-2-yl) piperazine-1-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 127, prepare title compound (0.065 g), with 4-(4-sec.-propyl piperazine-1-yl)-3-anisidine, substitute 4-((4-methylpiperazine-1-yl) methyl) aniline.Crude product is ground together with ethyl acetate, title compound is provided. 1H NMR(300 MHz, DMSO-d 6) δ 0.89-1.10(m, 6 H)2.59(s, 4 H)2.65-2.77(m, 1 H)2.97(s, 4 H)3.71-3.93(m, 3 H)6.95(s, 1 H)7.11(d, J=1.70 Hz, 1 H)7.37(s, 1 H)7.47-7.56(m, 1 H)7.57-7.69(m, 1 H)7.72-7.84(m, 3 H)9.13(s, 1 H)10.74(s, 1 H)。MS(ESI +)m/z 642.93(M+H) +。
Embodiment 138
6-(2-chloro-phenyl-)-2-{[4-(4-hydroxy piperidine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 130B, prepare title compound, with 1-(4-aminophenyl) piperidines-4-alcohol alternate embodiment 130A.Before HPLC, need not carry out aqueous solution processing. 1H NMR(400 MHz, CD 3OD)δ 2.09-1.92(m, 2H), 2.31-2.19(m, 2H), 3.68-3.58(m, 2H), 3.91-3.82(m, 2H), 4.15-4.07(m, 1H), 7.08(d, J=1.9 Hz, 1H), 7.63-7.53(m, 3H), 7.73-7.66(m, 3H), 7.92(d, J=1.9 Hz, 1H), 8.10-8.04(m, 2H), 9.22(s, 1H)。MS(ESI +)m/z 488.3(M+H) +。
Embodiment 139
6-(the chloro-6-fluorophenyl of 2-)-2-{[2-(dimethylamino)-2,3-dihydro-1H-indenes-5-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 130B, prepare title compound, with embodiment 95D and N 2, N 2-dimethyl-2,3-dihydro-1H-indenes-2,5-diamines is alternate embodiment 1E and embodiment 130A respectively.Before HPLC, need not carry out aqueous solution processing. 1H NMR(500 MHz, CD 3OD)δ 2.96(s, 6H), 3.30-3.16(m, 2H), 3.55-3.41(m, 2H), 4.21-4.14(m, 1H), 7.07(d, J=1.9 Hz, 1H), 7.43-7.29(m, 2H), 7.67-7.51(m, 3H), 7.87-7.81(m, 2H), 9.14(bs, 1H)。MS(ESI +)m/z 490.2(M+H) +。
Embodiment 140
6-(the chloro-6-fluorophenyl of 2-)-2-[(2'-methyl-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 130B, prepare title compound, with embodiment 95D and 2'-methyl-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-amine difference alternate embodiment 1E and embodiment 130A. 1H NMR(500 MHz, CD 3OD)δ 1.13-1.04(m, 1H), 1.27-1.13(m, 2H), 1.52-1.44(m, 1H), 3.09(s, 3H), 3.32-3.23(m, 1), 3.70-3.62(m, 1H), 4.78-4.49(m, 2H), 6.99-6.92(m, 1H), 7.08(d, J=1.9 Hz, 1H), 7.43-7.35(m, 1H), 7.54(d, J=8.2 Hz, 1H), 7.78-7.58(m, 3H), 7.88(s, 1H), 9.17(s, 1H)。MS(ESI +)m/z 502.2(M+H) +。
Embodiment 141
6-(the chloro-6-fluorophenyl of 2-)-2-{[4-(Isosorbide-5-Nitrae-Diazesuberane-1-yl)-3-aminomethyl phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 130B, prepare title compound, with embodiment 95D and embodiment 105B difference alternate embodiment 1E and embodiment 130A.Before HPLC, need not carry out aqueous solution processing. 1H NMR(500 MHz, CD 3OD)δ 2.16(dt, J=11.5, 5.9 Hz, 2H), 2.38(s, 3H), 3.18(dt, J=7.3, 3.7 Hz, 2H), 3.40(s, 4H), 3.52-3.43(m, 2H), 7.07(d, J=1.8 Hz, 1H), 7.20(bs, 1H), 7.38(td, J=8.9, 1.2 Hz, 1H), 7.67-7.47(m, 4H), 7.89-7.68(m, 1H), 9.12(s, 1H)。MS(ESI +)m/z 519.2(M+H) +。
Embodiment 142
2-[(2'-methyl-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl) amino]-6-(third-2-yl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 142A
3-sec.-propyl-7-(methylthio group) Kui Linpyrimido quinoline [4,5-d] pyrimidine-2,4 (1H, 3H)-diketone
As described in embodiment 1A, prepare title compound (0.4g), with n-Isopropyl isocyanate (2-isocyanatopropane), substitute the chloro-2-isocyanato of 1-benzene.MS(ESI +)m/z 253.0(M+H) +。
Embodiment 142B
The chloro-3-sec.-propyl-7-of 2-(methylthio group) Kui Linpyrimido quinoline [4,5-d] pyrimidine-4 (3H)-one
As described in embodiment 1B, prepare title compound (0.4 g), with embodiment 142A alternate embodiment 1A.MS(ESI +)m/z 271.06(M+H) +。
Embodiment 142C
2-(2,2-dimethoxy-ethyl is amino)-3-sec.-propyl-7-(methylthio group) Kui Linpyrimido quinoline [4,5-d] pyrimidine-4 (3H)-one
As described in embodiment 1C, prepare title compound (0.45 g), with embodiment 142B alternate embodiment 1B.MS(ESI +)m/z 340.3(M+H) +。
Embodiment 142D
2-(methyl sulfenyl)-6-(third-2-yl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 1D, prepare title compound (0.35g), with embodiment 142C alternate embodiment 1C.MS(ESI +)m/z 276.14(M+H) +。
Embodiment 142E
2-[(2'-methyl-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl) amino]-6-(third-2-yl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 127, prepare title compound (0.085 g), with embodiment 142D alternate embodiment 55D, with 2'-methyl-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9] alternative 4-((4-methylpiperazine-1-yl) methyl) aniline of-7'-amine.Crude product is ground together with ethyl acetate, title compound is provided. 1H NMR(300 MHz, DMSO-d 6) δ 0.72-1.01(m, 4 H)1.40-1.66(m, 6 H)2.25-2.40(m, 3 H)2.42-2.47(m, 2 H)3.53-3.71(m, 2 H)5.24-5.45(m, 1 H)6.74(d, J=8.72 Hz, 1 H)7.20(d, J=1.59 Hz, 1 H)7.46(s, 1 H)7.55(s, 1 H)7.69(d, J=1.59 Hz, 1 H)9.04(s, 1 H)10.48(s, 1 H)。MS(ESI +)m/z 416.2(M+H) +。
Embodiment 143
6-(2,6-dichlorophenyl)-2-{[4-(3-oxo piperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 109A, prepare title compound (0.03 g), the alternative 7'-amino-1'H-spiral shell of use 4-(4-aminophenyl) piperazine-2-ketone [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-2'(3'H)-formic acid tertiary butyl ester.Crude product is ground together with ethyl acetate, title compound is provided. 1H NMR(300 MHz, DMSO-d 6) δ 3.36-3.49(m, 2 H)3.63-3.80(m, 2 H)6.85-7.32(m, 3 H)7.45-7.96(m, 6 H)8.05(s, 1 H)9.11(s, 1 H)10.74(s, 1 H)。MS(ESI +)m/z 521.0(M+H) +。
Embodiment 144
6-(2-chloro-phenyl-)-2-{[4,4-dimethyl-2-(third-2-yl)-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 144A
2-sec.-propyl-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-amine
As described in embodiment 113A and embodiment 113B, prepare title compound, with acetone, substitute hexahydrobenzaldehyde.LC-MS: m/e=219(M+H) +。 1H NMR(400 MHz, CDCl 3), δ 7.07(d, J=8.0 Hz, 1 H), 6.53(dd, J=8.4 Hz, 2.8 Hz, 1 H), 6.34(d, J=2.4 Hz, 1 H), 3.59(s, 2 H), 3.48(br, 2 H), 2.82-2.88(m, 1 H), 2.39(s, 2 H), 1.23(s, 6 H), 1.08(d, J=6.4 Hz, 6 H)。
Embodiment 144B
6-(2-chloro-phenyl-)-2-{[4,4-dimethyl-2-(third-2-yl)-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 130B, prepare title compound, with embodiment 144A alternate embodiment 130A.Before HPLC, need not carry out aqueous solution processing. 1H NMR(400 MHz, CD 3OD)δ 1.51-1.48(m, 12H), 3.33-3.20(m, 1H), 3.55-3.52(m, 1H), 3.76(dt, J=13.2, 6.5 Hz, 1H), 4.45-4.41(m, 1H), 4.65-4.61(m, 1H), 7.06(d, J=1.8 Hz, 1H), 7.63-7.45(m, 4H), 7.72-7.64(m, 1H), 7.77(bs, 2H), 7.89-7.88(m, 1H), 9.16(s, 1H)。MS(ESI +)m/z 514.2(M+H) +。
Embodiment 145
6-(2-chloro-phenyl-)-2-{[4,4-dimethyl-2-(4,4,4-trifluoro butyl)-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 145A
4,4-dimethyl-2-(4,4,4-trifluoro butyl)-1,2,3,4-tetrahydroisoquinoline-7-amine
As described in embodiment 113A and embodiment 113B, prepare title compound, with 4,4,4-trifluoro butyraldehyde, substitute hexahydrobenzaldehyde.LC-MS: m/e=287(M+H) +。 1H NMR(400 MHz, CDCl 3), δ 7.09(d, J=8.4 Hz, 1 H), 6.54(dd, J=8.0, 2.4 Hz, 1 H), 6.33(d, J=2.0 Hz, 1 H), 3.51(br, 2 H), 3.47(s, 2 H), 2.48(t, J=6.8 Hz, 2 H), 2.36(s, 2 H), 2.19-2.25(m, 2 H), 1.77-1.81(m, 2 H), 1.25(s, 6 H)。
Embodiment 145B
6-(2-chloro-phenyl-)-2-{[4,4-dimethyl-2-(4,4,4-trifluoro butyl)-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 130B, prepare title compound, with embodiment 145A alternate embodiment 130A.Before HPLC, need not carry out aqueous solution processing. 1H NMR(400 MHz, CD 3OD)δ 1.50(s, 6H), 2.18(bs, 2H), 2.47-2.31(m, 2H), 3.63-3.37(m, 4H), 4.55(bs, 2H), 7.05(d, J=1.9 Hz, 1H), 7.62-7.53(m, 4H), 7.77-7.66(m, 3H), 7.88(d, J=1.9 Hz, 1H), 9.17(s, 1H)。MS(ESI +)m/z 582.3(M+H) +。
Embodiment 146
6-(2-chloro-phenyl-)-2-[(1,1,2-trimethylammonium-2,3-dihydro-1H-isoindole-5-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 130B, prepare title compound, with 1,1,2-trimethylammonium isoindoline-5-amine alternate embodiment 130A. 1H NMR(400 MHz, CD 3OD)δ 1.55(s, 3H), 1.83(s, 3H), 3.03(s, 3H), 4.66-4.57(m, 1H), 4.91-4.77(m, 1H), 7.07(d, J=1.9 Hz, 1H), 7.45-7.43(m, 1H), 7.63-7.52(m, 3H), 7.73-7.64(m, 1H), 7.79(bs, 1H), 7.89(d, J=1.9 Hz, 1H), 8.00(s, 1H), 9.19(s, 1H)。MS(ESI +)m/z 472.2(M+H) +。
Embodiment 147
6-(2-chloro-phenyl-)-2-[(1,1,2,3,3-pentamethyl--2,3-dihydro-1H-isoindole-5-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 130B, prepare title compound, with 1,1,2,3,3-pentamethyl-isoindoline-5-amine alternate embodiment 130A. 1H NMR(500 MHz, CD 3OD)δ 1.72-1.65(m, 6H), 1.91-1.74(m, 6H), 2.99(s, 3H), 7.08(d, J=1.9 Hz, 1H), 7.49-7.43(m, 1H), 7.62-7.51(m, 3H), 7.72-7.66(m, 1H), 7.92-7.80(m, 3H), 9.21(s, 1H)。MS(ESI +)m/z 500.2(M+H) +。
Embodiment 148
6-(2,6-dichlorophenyl)-2-{[3-methoxyl group-4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 127, prepare title compound (0.105 g), with 3-methoxyl group-4-(4-methylpiperazine-1-yl) aniline, substitute 4-((4-methylpiperazine-1-yl) methyl) aniline.Crude product is dissolved in the trifluoroacetic acid of methylene dichloride and equivalent.After stirring one hour, concentrated this mixture.Crude product is dissolved in methyl alcohol, and processes with excessive 2N HCl/ diethyl ether.Further with ether, dilute this mixture, stir, filter, title compound is provided. 1H NMR(300 MHz, DMSO-d 6) δ 2.77-2.89(m, 3 H)2.91-3.09(m, 2 H)3.11-3.32(m, 2 H)3.43-3.55(m, 4 H)3.80-3.90(m, 3 H)6.97-7.07(m, J=2.71 Hz, 1 H)7.12(d, J=2.03 Hz, 1 H)7.37-7.49(m, J=2.03 Hz, 1 H)7.55(s, 1 H)7.58-7.70(m, 1 H)7.71-7.84(m, 3 H)9.15(s, 1 H)10.30(s, 1 H)10.79(s, 1 H)。MS(ESI +)m/z 551.2. .(M+H) +。
Embodiment 149
6-(2,6-dichlorophenyl)-2-(4-[3-(diethylamino) propoxy-] and-3-fluorophenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 127, prepare title compound (0.079 g), with 4-(3-(diethylamino) propoxy-)-3-fluoroaniline, substitute 4-((4-methylpiperazine-1-yl) methyl) aniline.Crude product is dissolved in the trifluoroacetic acid of methylene dichloride and equivalent.This mixture is stirred 1 hour, and concentrated.Crude product is dissolved in methyl alcohol, and processes with excessive 2N HCl/ diethyl ether.Further with ether, dilute this mixture, stir, filter, title compound is provided. 1H NMR(300 MHz, DMSO-d 6) δ 1.24(d, 6 H)2.14(d, 2 H)3.16(d, 6 H)4.16(d, 2 H)7.13(d, J=1.59 Hz, 1 H)7.26(t, J=8.93 Hz, 1 H)7.55-7.70(m, 2 H)7.70-7.88(m, 4 H)9.18(s, 1 H)9.78(s, 1 H)10.89(s, 1 H)。MS(ESI +)m/z 570.3(M+H) +。
Embodiment 150
6-(2,6-dichlorophenyl)-2-[(1,1,2-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-6-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
In embodiment 55D (75 mg, 0.198 mmol) and metachloroperbenzoic acid (53.3 mg, 0.238 mmol), add 2 mL methylene dichloride.This reaction is stirred 15 minutes, add 1,1,2-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-6-amine (45 mg, 0.238 mmol), then adds trifluoroacetic acid (0.031 mL, 0.397 mmol).This mixture is at room temperature stirred and spent the night, with ethyl acetate dilution, use saturated NaHCO 3the aqueous solution, water and salt water washing, use MgSO 4dry, concentrated.Use preparative HPLC purifying crude product (on Phenomenex Luna C8 (2) 5 μ m 100 AXIA posts (30mm * 75mm)).Use the gradient of acetonitrile (A) and 0.1% trifluoroacetic acid/water (B), flow velocity 50 mL/min (0-0.5 min, 10% A; 0.5-7.0 min linear gradient, 10-95% A; 7.0-10.0 min, 95% A; 10.0-12.0 min linear gradient, 95-10% A).Tfa salt is dissolved in methyl alcohol, with excessive 2M HCl/ diethyl ether, processes, stir, until start to form solid.With ether, dilute this mixture, stir 10 minutes, filter, title compound is provided. 1H NMR(300 MHz, DMSO-d 6) δ 1.60(d, 3 H)1.76(d, 3 H)2.83(d, 3 H)3.05(d, 1 H)3.32(d, 1 H)3.55(d, 2 H)7.14(d, J=1.59 Hz, 1 H)7.51(d, J=8.73 Hz, 1 H)7.57-7.91(m, 6 H)9.19(s, 1 H)10.61-11.08(m, 2 H)。MS(ESI +)m/z 520.2(M+H) +。
Embodiment 151
2-(4-[(1S, 4S) and-2,5-diazabicyclo [2.2.1] heptan-2-yl] phenyl } amino)-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 109A, prepare title compound (0.11 g), with (1S, 4S)-5-(4-aminophenyl)-2,5-diazabicyclo [2.2.1] heptane-2-formic acid tertiary butyl ester substitutes 7'-amino-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-2'(3'H)-formic acid tertiary butyl ester.Crude product is dissolved in 1:1 methylene dichloride/TFA to 1 hour, uses preparative HPLC purifying (on Phenomenex Luna C8 (2) 5 μ m 100 AXIA posts (30mm * 75mm)).Use the gradient of acetonitrile (A) and 0.1% trifluoroacetic acid/water (B), flow velocity 50 mL/min (0-0.5 min, 10% A; 0.5-7.0 min linear gradient, 10-95% A; 7.0-10.0 min, 95% A; 10.0-12.0 min linear gradient, 95-10% A).The tfa salt obtaining is dissolved in methyl alcohol, and processes 20 minutes with 2N HCl/ diethyl ether.To precipitate with diethyl ether dilution, filter, title compound will be provided. 1H NMR(300 MHz, DMSO-d 6) δ 1.83-2.23(m, 2 H)3.16-3.38(m, 2 H)3.49-3.73(m, 2 H)4.29-4.70(m, 2 H)6.61-6.83(m, 2 H)7.11(s, 1 H)7.43-7.58(m, 1 H)7.58-7.68(m, 1 H)7.68-7.84(m, 4 H)8.71(s, 1 H)9.09(s, 1 H)9.28(s, 1 H)10.69(s, 1 H)。MS(ESI +)m/z 519(M+H) +。
Embodiment 152
6-(2,6-dichlorophenyl)-2-[(2,4,4-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-7-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 150, prepare title compound (0.095 g), with 2,4,4-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-7-amine substitutes 1,1,2-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-6-amine.Crude product is ground together with ethyl acetate, be dissolved in methyl alcohol, with excessive 2M HCl/ diethyl ether, process, stir, until start to form solid.With ether, dilute this mixture, stir 10 minutes, filter, title compound is provided. 1H NMR(300 MHz, DMSO-d 6) δ 1.32-1.38(m, 3 H)1.42-1.47(m, 3 H)2.95-3.03(m, 3 H)3.13-3.34(m, 2 H)4.28-4.58(m, 2 H)7.07-7.19(m, 1 H)7.49-7.91(m, 7 H)9.18(s, 1 H)10.03(s, 1 H)10.92(s, 1 H)。MS(ESI +)m/z 520.2(M+H) +。
Embodiment 153
6-(2,6-dichlorophenyl)-2-{[4-(4,4-difluoro piperidin-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 109A, prepare title compound (0.08 g), the alternative 7'-amino-1'H-spiral shell of use 4-(4,4-difluoro piperidin-1-yl) aniline [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-2'(3'H)-formic acid tertiary butyl ester.With Analogix 280 (SF 12-24 post), carry out chromatogram purification, use 10% to 70% ethyl acetate/hexane gradient elution 30 minutes. 1H NMR(300 MHz, DMSO-d 6) δ 1.92-2.21(m, 4 H)3.33-3.40(m, 4 H)6.94-7.20(m, 3 H)7.48-7.96(m, 6 H)9.04-9.18(m, 1 H)10.60-10.83(m, 1 H)。MS(ESI +)m/z 542.3(M+H) +。
Embodiment 154
6-(2,6-dichlorophenyl)-2-{[4-(3,3-difluoro piperidin-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 109A, prepare title compound (0.09 g), the alternative 7'-amino-1'H-spiral shell of use 4-(3,3-difluoro piperidin-1-yl) aniline [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-2'(3'H)-formic acid tertiary butyl ester.With Analogix 280 (SF 12-24 post), carry out chromatogram purification, use 10% to 70% ethyl acetate/hexane gradient elution 30 minutes. 1H NMR(300 MHz, DMSO-d 6) δ 1.71-1.92(m, 2 H)1.93-2.16(m, 2 H)3.22(d, J=4.75 Hz, 2 H)3.43(q, J=12.09 Hz, 2 H)6.94-7.22(m, 3 H)7.49-7.98(m, 6 H)9.11(s, 1 H)10.73(s, 1 H)MS(ESI +)m/z 542.3(M+H) +。
Embodiment 155
6-(2,6-dichlorophenyl)-2-(the fluoro-4-[4-of 3-(third-2-yl) piperazine-1-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 150, prepare title compound (0.06 g), the alternative 7'-amino-1'H-spiral shell of the use fluoro-4-of 3-(4-sec.-propyl piperazine-1-yl) aniline [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-2'(3'H)-formic acid tertiary butyl ester.Crude product is ground together with ethyl acetate, filter, high vacuum dry, provides title compound. 1H NMR(300 MHz, DMSO-d 6) δ 1.00(t, J=7.34 Hz, 6 H)2.55-2.64(m, 4 H)2.65-2.75(m, 1 H)3.00(s, 4 H)6.93-7.29(m, 2 H)7.52-7.96(m, 6 H)9.16(s, 1 H)10.87(s, 1 H)。MS(ESI +)m/z 567.2(M+H) +。
Embodiment 156
6-(2,6-dichlorophenyl)-2-{[4-(piperazine-1-yl)-3-(trifluoromethyl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 156A
4-[4-{[6-(2,6-dichlorophenyl)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino }-2-(trifluoromethyl) phenyl] piperazine-1-formic acid tertiary butyl ester
As described in embodiment 109A, prepare title compound (0.09 g), by 4-(4-amino-2-(trifluoromethyl) phenyl) piperazine-1-formic acid tertiary butyl ester, substitute 7'-amino-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-2'(3'H)-formic acid tertiary butyl ester.With Analogix 280 (SF12-24 post), carry out chromatographic separation, use 10% to 70% ethyl acetate/hexane gradient elution 30 minutes, title compound is provided.MS(ESI+)m/z 675.1(M+H)+。
Embodiment 156B
6-(2,6-dichlorophenyl)-2-{[4-(piperazine-1-yl)-3-(trifluoromethyl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 109B, prepare title compound (0.08g), with embodiment 156A alternate embodiment 109A.Tfa salt is dissolved in methyl alcohol, with excessive 2M HCl/ diethyl ether, processes, stir, until start to form solid.With ether, dilute this mixture, stir 10 minutes, filter, title compound is provided. 1H NMR(300 MHz, DMSO-d 6) δ 3.09(d, J=4.41 Hz, 4 H)3.15-3.28(m, 4 H)7.16(d, J=1.70 Hz, 1 H)7.52-7.72(m, 2 H)7.70-7.88(m, 3 H)8.17(s, 2 H)8.97(s, 2 H)9.22(s, 1 H)11.11(s, 1 H)。MS(ESI +)m/z 575.2(M+H) +。
Embodiment 157
6-(2-chloro-phenyl-)-2-{[4-(4-methylpiperazine-1-yl)-3-(third-2-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 157A
1-methyl-4-(4-nitro-2-(third-1-alkene-2-yl) phenyl) piperazine
By 1-(the bromo-4-nitrophenyl of 2-)-4-methylpiperazine (0.810 g, 2.70 mmol), tetrakis triphenylphosphine palladium (0) (0.094 g, 0.081 mmol) and tributyl (third-1-alkene-2-yl) stannane (0.983 g, 2.97 mmol) 1, mixture in 4-diox (30 mL) is degassed, and 105 ℃ of heated overnight.After cooling, filter this suspension, concentrated, purifying on 40 g posts, is used ISCO Companion flash chromatographic system, with methanol/ethyl acetate (5:95 to 10:90) wash-out, provides title compound.
Embodiment 157B
3-sec.-propyl-4-(4-methylpiperazine-1-yl) aniline
In 50 mL pressure bottles, Ra-Ni water slurry (10 mg) and tetrahydrofuran (THF) (10 mL)/trifluoroethanol (10 mL) are joined in embodiment 157A (20 mg, 0.077 mmol).In the atmosphere of hydrogen of 30 psi, at room temperature, stir this mixture 16 hours.Filter this reaction mixture, concentrated, title compound is provided.
Embodiment 157C
6-(2-chloro-phenyl-)-2-{[4-(4-methylpiperazine-1-yl)-3-(third-2-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 130B, prepare title compound, with embodiment 157B alternate embodiment 130A.Before HPLC purifying, need not carry out aqueous solution processing. 1H NMR(400 MHz, CD 3OD)δ 1.29(s, 3H), 1.30(s, 3H), 3.00(s, 3H), 3.24-3.07(m, 4H), 3.42-3.26(m, 2H), 3.61-3.58(m, 3H), 7.06(d, J=1.8 Hz, 1H), 7.27(d, J=7.1 Hz, 1H), 7.62-7.46(m, 3H), 7.74-7.65(m, 3H), 7.82(bs, 1H), 9.14(s, 1H)。MS(ESI +)m/z 529.3(M+H) +。
Embodiment 158
2-{[4-(4-ethanoyl piperazine-1-yl) phenyl] amino }-6-(the chloro-6-fluorophenyl of 2-) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 123B, prepare title compound, with embodiment 95C and 1-(4-(4-aminophenyl) piperazine-1-yl) ethyl ketone difference alternate embodiment 123A and 4-(4-methylpiperazine-1-yl) aniline. 1H NMR(400 MHz, CD 3OD)δ 2.18(s, 3H), 3.41-3.33(m, 4H), 3.87-3.74(m, 4H), 7.09(d, J=1.9 Hz, 1H), 7.29-7.23(m, 2H), 7.44-7.34(m, 1H), 7.57-7.47(m, 1H), 7.63(td, J=8.3, 5.7 Hz, 1H), 7.83-7.74(m, 2H), 7.90-7.85(m, 1H), 9.16(s, 1H)。MS(ESI +)m/z 533.3(M+H) +。
Embodiment 159
6-(the chloro-6-fluorophenyl of 2-)-2-[(4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 123B, prepare title compound, with embodiment 95C and 4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-amine is alternate embodiment 123A and 4-(4-methylpiperazine-1-yl) aniline respectively. 1H NMR(400 MHz, CD 3OD)δ 1.37(s, 3H), 1.41(s, 3H), 4.21-4.09(m, 2H), 5.25-5.23(m, 2H), 7.08(t, J=1.8 Hz, 1H), 7.30-7.20(m, 2H), 7.42-7.34(m, 1H), 7.56-7.50(m, 1H), 7.65-7.59(m, 2H), 7.99(dd, J=4.0, 2.0 Hz, 1H), 9.15(d, J=5.0 Hz, 1H)。MS(ESI +)m/z 490.3(M+H) +。
Embodiment 160
6-(the chloro-4-fluorophenyl of 2,6-bis-)-2-(2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-base amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 160A
7'-{[6-(the chloro-4-fluorophenyl of 2,6-bis-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino }-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-2'(3'H)-formic acid tertiary butyl ester
By embodiment 123A (600.0 mg, 1.514 mmol) and metachloroperbenzoic acid (407 mg, 1.817 mmol) at CH 2cl 2mixture in (14 mL) stirs 20 minutes.By 7'-amino-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-2'(3'H)-formic acid tertiary butyl ester (499 mg, 1.817 mmol) joins in this reaction mixture.After 25 minutes, by ethyl acetate, dilute this reaction mixture, use saturated NaHCO 3the aqueous solution and salt water washing.By organic layer MgSO 4dry, filter, concentrated, purifying on 40 g posts, is used ISCO Companion flash chromatographic system, with hexane/ethyl acetate (6:4 to 4:6) wash-out, provides title compound.
Embodiment 160B
6-(the chloro-4-fluorophenyl of 2,6-bis-)-2-(2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-base amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
CH to embodiment 160A (0.855 g, 1.374 mmol) 2cl 2in (10 mL) solution, add trifluoroacetic acid (1.058 mL, 13.74 mmol).This reaction mixture is stirred 7 hours, concentrated.Resistates is dissolved in 5 mL methyl alcohol, with 2M HCl/ diethyl ether, processes at leisure, until start to form precipitation.Add diethyl ether, and by this suspension agitation 15 minutes, filter, with ether washing, dry by bake oven, the HCl salt of title compound is provided. 1H NMR(300 MHz, DMSO-d 6)δ 1.11(s, 4H), 3.27(dd, J=4.4, 2.2 Hz, 2H), 4.46(s, 2H), 6.93(d, J=9.0 Hz, 1H), 7.14(d, J=1.8 Hz, 1H), 7.82-7.63(m, 2H), 7.91-7.84(m, 2H), 9.17(s, 1H), 9.37(bs, 1H), 10.90(bs, 1H)。MS(ESI+)m/z 522.3(M+H) +。
Embodiment 161
6-(2-chloro-phenyl-)-2-[(2-ethyl-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 161A
2-ethyl-4,4-dimethyl-7-nitro-1,2,3,4-tetrahydroisoquinoline
Monobromethane (0.75 g, 6.88 mmol) is joined to 4,4-dimethyl-7-nitro-1,2,3,4-tetrahydroisoquinoline (1.4 g, 6.79 mmol) and K 2cO 3in DMF (80 mL) solution of (2 g, 14.47 mmol).This mixture is stirred 4 hours at 50 ℃.Solvent removed in vacuo, obtains resistates, is used silica gel chromatography, with 10% ethyl acetate/heptane wash-out, provides title compound.
Embodiment 161B
2-ethyl-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-amine
As described in embodiment 113B, prepare title compound, with embodiment 161A alternate embodiment 113A.LC-MS: m/e=205(M+H) +。 1H NMR(400 MHz, CDCl 3), δ 7.08(d, J=8.4 Hz, 1 H), 6.53(dd, J=8.4 Hz, 2.4 Hz, 1 H), 6.33(d, J=2.4 Hz, 1 H), 3.48(s, 4 H), 2.49(q, J=6.8 Hz, 14.0 Hz, 2 H), 2.36(s, 2 H), 1.25(s, 6 H), 1.14(t, J=7.2 Hz, 3 H)。
Embodiment 161C
6-(2-chloro-phenyl-)-2-[(2-ethyl-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 130B, prepare title compound, with embodiment 161B alternate embodiment 130A.Before HPLC, need not carry out aqueous solution processing. 1H NMR(400 MHz, CD 3OD)δ 1.53-1.45(m, 9H), 3.31-3.26(m, 1H), 3.43(q, J=7.3 Hz, 2H), 3.65-3.56(m, 1H), 4.63-4.39(m, 2H), 7.06(d, J=1.9 Hz, 1H), 7.62-7.53(m, 4H), 7.80-7.62(m, 3H), 7.88(d, J=1.9 Hz, 1H), 9.16(s, 1H)。MS(ESI +)m/z 500.2(M+H) +。
Embodiment 162
6-(2-chloro-phenyl-)-2-{[4,4-dimethyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 162A
4,4-dimethyl-7-nitro-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline
By trichlorine methylsulfonic acid 2,2,2-trifluoroethyl ester (1.8 g, 6.40 mmol) joins 4,4-dimethyl-7-nitro-1,2,3,4-tetrahydroisoquinoline (0.8 g, 3.88 mmol) and sodium bicarbonate (0.66 g, 7.86 mmol) in DMF (50 mL) solution.This reaction mixture is stirred 16 hours at 60 ℃.Concentrated this mixture, and by CH 2cl 2(70 mL) and water (70 mL) join in resistates.After separating, uses CH 2cl 2again extract water layer.The organic layer merging with the saturated NaCl aqueous solution (1 x 150mL) washing, uses Na 2sO 4dry, filter, concentrated, title compound is provided.
Embodiment 162B
4,4-dimethyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-7-amine
As described in embodiment 113B, prepare title compound, with embodiment 161A alternate embodiment 113A.LC-MS: m/e=259(M+H) +。 1H NMR(400 MHz, CDCl 3), δ 7.09(d, J=8.4 Hz, 1 H), 6.50(dd, J=8.4 Hz, 2.4 Hz, 1 H), 6.30(d, J=2.4 Hz, 1 H), 3.75(s, 2 H), 3.51(br, 2 H), 3.10(q, J=9.6 Hz, 2 H), 2.62(s, 2 H), 1.26(s, 6 H)。
Embodiment 162C
6-(2-chloro-phenyl-)-2-{[4,4-dimethyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 130B, prepare title compound, with embodiment 162B alternate embodiment 130A.Before HPLC, need not carry out aqueous solution processing. 1H NMR(400 MHz, CD 3OD)δ 1.33(s, 6H), 2.72(s, 2H), 3.29-3.22(m, 2H), 3.89(s, 2H), 7.06(d, J=1.5 Hz, 1H), 7.44-7.38(m, 2H), 7.64-7.48(m, 4H), 7.72-7.64(m, 1H), 7.83(s, 1H), 9.19(d, J=43.2 Hz, 1H)。MS(ESI+)m/z 554.3(M+H) +。
Embodiment 163
6-(2-chloro-phenyl-)-2-(2-[4-(1H-imidazoles-1-yl) benzyl] and-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 163A
2-(4-(1H-imidazoles-1-yl) benzyl)-4,4-dimethyl-7-nitro-1,2,3,4-tetrahydroisoquinoline
As described in embodiment 113A, prepare title compound, with 4-(1H-imidazoles-1-yl) phenyl aldehyde, substitute hexahydrobenzaldehyde.
Embodiment 163B
2-(4-(1H-imidazoles-1-yl) benzyl)-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-amine
In 95% ethanol (20 mL) solution of embodiment 163A (1.45 g, 4.00 mmol), add zinc (2 g, 30.6 mmol) and acetic acid (4 mL, 69.9 mmol).This reaction mixture is stirred 4 hours at 50 ℃.By saturated NaHCO 3the aqueous solution (200 mL) and CH 2cl 2(200 mL) joins in this reaction mixture, and filters this suspension.Use CH 2cl 2(200 mL) extracts water layer.By saturated NaCl for organic layer (the 1 x 300 mL) washing merging, use Na 2sO 4dry, filter, concentrated.Use Chemflash system purifying crude product, use 120 g C18 posts, with 40-80% methanol/water (0.8 g (NH 4) 2cO 3, in 1L water) and wash-out, title compound is provided.LC-MS: m/e=333(M+H) +。 1H NMR(400 MHz, DMSO-d 6), δ 8.25(s, 1 H), 7.73(s, 1 H), 7.62(d, J=8.4 Hz, 2 H), 7.49(d, J=8.4 Hz, 2 H), 7.11(s, 1 H), 6.97(d, J=8.4 Hz, 1 H), 6.41(dd, J=8.4 Hz, 2.0 Hz, 1 H), 6.16(d, J=2.0 Hz, 1 H), 4.76(s, 2 H), 3.62(s, 2 H), 3.43(s, 2 H), 2.31(s, 2 H), 1.15(s, 6 H)。
Embodiment 163C
6-(2-chloro-phenyl-)-2-(2-[4-(1H-imidazoles-1-yl) benzyl] and-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 130B, prepare title compound, with embodiment 163B alternate embodiment 130A.Before HPLC, need not carry out aqueous solution processing. 1H NMR(400 MHz, CD 3OD)δ 1.45(s, 6H), 3.42(s, 2H), 4.56(bs, 2H), 4.69(s, 2H), 7.06(d, J=1.8 Hz, 1H), 7.62-7.51(m, 4H), 7.81-7.66(m, 4H), 7.94-7.85(m, 5H), 8.13(t, J=1.8 Hz, 1H), 9.18(s, 1H), 9.48(t, J=1.4 Hz, 1H)。MS(ESI +)m/z 628.3(M+H) +。
Embodiment 164
2-(2-[(1-benzyl piepridine-4-yl) and methyl]-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl } amino)-6-(2-chloro-phenyl-) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 164A
2-((1-benzyl piepridine-4-yl) methyl)-4,4-dimethyl-7-nitro-1,2,3,4-tetrahydroisoquinoline
As described in embodiment 113A, prepare title compound, with 1-benzyl piepridine-4-formaldehyde, substitute hexahydrobenzaldehyde.
Embodiment 164B
2-((1-benzyl piepridine-4-yl) methyl)-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-amine
As described in embodiment 163B, prepare title compound, with embodiment 164A alternate embodiment 163A.LC-MS: m/e=364(M+H) +。 1H NMR(400 MHz, CDCl 3), δ 7.22-7.32(m, 5 H), 7.07(d, J=8.4 Hz, 1 H), 6.53(dd, J=8.4 Hz, 2.4 Hz, 1 H), 6.32(d, J=2.4 Hz, 1 H), 3.48-3.51(m, 4 H), 3.44(s, 2 H), 2.88(d, J=9.2 Hz, 2 H), 2.32(s, 2 H), 2.26(d, J=7.2 Hz, 2 H), 1.96(t, J=7.2 Hz, 2 H), 1.78(d, J=12.4 Hz, 2 H), 1.52-1.62(m, 1 H), 1.26-1.32(m, 2 H), 1.23(s, 6 H)。
Embodiment 164C
2-(2-[(1-benzyl piepridine-4-yl) and methyl]-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl } amino)-6-(2-chloro-phenyl-) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 130B, prepare title compound, with embodiment 164B alternate embodiment 130A.Before HPLC purifying, need not carry out aqueous solution processing. 1H NMR(400 MHz, CD 3OD)δ 1.50(s, 6H), 1.69(dd, J=24.1, 12.1 Hz, 2H), 2.10(d, J=14.1 Hz, 2H), 2.41(bs, 1H), 3.10(t, J=12.5 Hz, 2H), 3.38-3.31(m, 2H), 3.60-3.47(m, 4H), 4.35(s, 2H), 4.55(s, 2H), 7.06(d, J=1.9 Hz, 1H), 7.63-7.39(m, 9H), 7.81-7.64(m, 3H), 7.88(d, J=1.5 Hz, 1H), 9.17(s, 1H)。MS(ESI +)m/z 659.2(M+H) +。
Embodiment 165
2-[(2'-ethanoyl-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl) amino]-6-(the chloro-4-fluorophenyl of 2,6-bis-) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
By embodiment 160B (0.080 g, 0.134 mmol), acetic acid (0.012 mL, 0.202 mmol), benzotriazole-1-base oxygen base tripyrrole alkane Ji Phosphonium hexafluorophosphate (0.105 g, 0.202 mmol) and tetrahydrofuran (THF) (4 mL) solution stirring of triethylamine (0.094 mL, 0.672 mmol) spend the night.By ethyl acetate, dilute this reaction mixture, and use saturated NaHCO 3the aqueous solution and salt water washing.By organic layer MgSO 4dry, filter, concentrated, purifying on 4 g posts, is used ISCO Companion flash chromatographic system, by hexane/ethyl acetate (1:9), to 100% eluent ethyl acetate, provides title compound. 1H NMR(400 MHz, CD 3OD)δ 1.10-0.98(m, 4H), 2.17(s, 1.7H), 2.23(s, 1.3H), 3.63(d, J=4.0 Hz, 2H), 4.89(s, 2H), 6.90(bs, 1H), 7.08(d, J=1.8 Hz, 1H), 7.63-7.45(m, 4H), 7.86(bs, 1H), 9.15(bs, 1H)。MS(ESI +)m/z 564.2(M+H) +。
Embodiment 166
6-(2,6-dichlorophenyl)-2-{[4-(4-hydroxy piperidine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 109A, prepare title compound (0.02 g), the alternative 7'-amino-1'H-spiral shell of use 1-(4-aminophenyl) piperidines-4-alcohol [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-2'(3'H)-formic acid tertiary butyl ester.From crude product reaction mixture, grind together with dichloromethane/ethyl acetate, obtain final compound. 1H NMR(300 MHz, DMSO-d 6) δ 1.21-1.32(m, 1 H)1.57(s, 2 H)1.86(s, 2 H)2.80-3.06(m, 4 H)7.11(d, J=1.59 Hz, 2 H)7.46-7.99(m, 7 H)9.12(s, 1 H)10.55-10.94(m, J=27.77 Hz, 1 H)。MS(ESI +)m/z 522.2(M+H) +。
Embodiment 167
2-[(4-cyclohexyl phenyl) amino]-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 109A, prepare title compound (0.07 g), the alternative 7'-amino-1'H-spiral shell of use 4-cyclohexyl aniline [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-2'(3'H)-formic acid tertiary butyl ester.With Analogix 280 (SF 12-24 post), carry out chromatographic separation, use 10% to 70% ethyl acetate/hexane gradient elution 30 minutes, title compound is provided. 1H NMR(300 MHz, DMSO-d 6) δ 1.31-1.51(m, 5 H)1.63-1.90(m, 6 H)7.11(d, J=1.70 Hz, 1 H)7.27(d, J=7.80 Hz, 2 H)7.49-7.95(m, 6 H)9.14(s, 1 H)10.80(s, 1 H)。MS(ESI +)m/z 505.4(M+H) +。
Embodiment 168
6-(2,6-dichlorophenyl)-2-{[4-(pyrrolidin-3-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 168A
3-(4-{[6-(2,6-dichlorophenyl)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } phenyl) tetramethyleneimine-1-formic acid tertiary butyl ester
As described in embodiment 109A, prepare title compound (0.09 g), the alternative 7'-amino-1'H-spiral shell of use 4-(4-aminophenyl) piperazine-2-ketone [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-2'(3'H)-formic acid tertiary butyl ester.With Analogix 280 (SF 12-24 post), carry out chromatographic separation, use 10% to 70% ethyl acetate/hexane gradient elution 30 minutes, title compound is provided.MS(ESI +)m/z 591.9(M+H) +。
Embodiment 168B
6-(2,6-dichlorophenyl)-2-{[4-(pyrrolidin-3-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 109B, prepare title compound (0.085g), with embodiment 168A alternate embodiment 109A.Tfa salt is dissolved in methyl alcohol, with excessive 2M HCl/ diethyl ether, processes, stir, until start to form solid.With diethyl ether, dilute this mixture, stir 10 minutes, filter. 1H NMR(300 MHz, DMSO-d 6) δ 1.93(d, 1 H)2.37(d, 1 H)3.06(d, 1 H)3.17-3.34(m, 3 H)7.13(d, J=1.59 Hz, 1 H)7.40(d, J=8.33 Hz, 2 H)7.57-7.70(m, 1 H)7.70-7.98(m, 5 H)9.17(s, 3 H)10.89(s, 1 H)。MS(ESI +)m/z 492.2(M+H) +。
Embodiment 169
6-(2,6-dichlorophenyl)-2-{[4-(morpholine-4-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 109A, prepare title compound (0.085 g), the alternative 7'-amino-1'H-spiral shell of use 4-morpholino aniline [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-2'(3'H)-formic acid tertiary butyl ester.With Analogix 280 (SF 12-24 post), carry out chromatographic separation, use 50% to 100% ethyl acetate/hexane gradient elution 30 minutes. 1H NMR(300 MHz, DMSO-d 6) δ 3.11(s, 4 H)3.65-3.83(m, 4 H)7.01(s, 2 H)7.11(d, J=1.59 Hz, 1 H)7.45-7.96(m, 6 H)9.10(s, 1 H)10.73(s, 1 H)。MS(ESI +)m/z 508.3(M+H) +。
Embodiment 170
6-(2,6-dichlorophenyl)-2-{[4,4-dimethyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 150, prepare title compound (0.09 g), with 4,4-dimethyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-7-amine substitutes 1,1,2-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-6-amine.With Analogix 280 (SF 12-24 post), carry out chromatographic separation, use 10% to 70% ethyl acetate/hexane gradient elution 30 minutes. 1H NMR(300 MHz, DMSO-d 6) δ 1.27(s, 6 H)2.61-2.76(m, 2 H)3.33-3.49(m, 2 H)3.85(s, 2 H)7.12(d, J=1.59 Hz, 1 H)7.34-7.54(m, J=8.33 Hz, 2 H)7.58-7.70(m, 2 H)7.71-7.83(m, 3 H)9.15(s, 1 H)10.78(s, 1 H)。MS(ESI +)m/z 588.3(M+H) +。
Embodiment 171
2-{[2'-(cyclopropyl carbonyl)-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl] amino-6-(the chloro-4-fluorophenyl of 2,6-bis-) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 165, prepare title compound, with cyclopropane-carboxylic acid, substitute acetic acid.With HPLC, purify crude product (referring to the scheme of embodiment 1F), the trifluoroacetate of title compound is provided. 1H NMR(400 MHz, DMSO-d 6)δ 0.83-0.68(m, 4H), 1.13-0.90(m, 4H), 2.22-2.03(m, 1H), 3.56(s, 0.8H), 3.81(s, 1.2H), 4.79(s, 1.4H), 5.05(s, 0.6H), 6.93-6.70(m, 1H), 7.13(d, J=1.8 Hz, 1H), 7.69-7.56(m, 2H), 7.90-7.80(m, 3H), 9.16(s, 1H), 10.84(bs, 1H)。MS(ESI +)m/z 590.2(M+H) +。
Embodiment 172
6-(the chloro-4-fluorophenyl of 2,6-bis-)-2-{[2'-(methylsulfonyl)-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl] amino imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Mixture by embodiment 160B (0.065 g, 0.109 mmol), methylsulfonyl chloride (0.013 mL, 0.164 mmol) and triethylamine (0.076 mL, 0.546 mmol) in DMF (2 mL) stirs 2 hours.Water is joined in this reaction mixture.Solid filtering by obtaining, washes with water, further with HPLC, purifies (referring to the scheme of embodiment 1F), and the trifluoroacetate of title compound is provided. 1H NMR(400 MHz, CD 3OD)δ 1.10-1.04(m, 4H), 2.90(s, 3H), 3.43(s, 2H), 4.63(s, 2H), 6.86(bs, 1H), 7.09(d, J=1.8 Hz, 1H), 7.66-7.51(m, 4H), 7.84(bs, 1H), 9.14(s, 1H)。MS(ESI +)m/z 600.2(M+H) +。
Embodiment 173
6-(the chloro-4-fluorophenyl of 2,6-bis-)-2-{[6-(piperazine-1-yl) pyridin-3-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
According to embodiment 160A and the described general method of embodiment 160B, prepare title compound, in embodiment 160A, with 4-(5-aminopyridine-2-yl) piperazine-1-formic acid tertiary butyl ester (64.9 mg, 0.233 mmol) substitute 7'-amino-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-2'(3'H)-formic acid tertiary butyl ester.At 35 ℃, carry out deprotection steps and spend the night, do not change final trifluoroacetate into HCl salt. 1H NMR(400 MHz, CD 3OD)δ 3.38(t, J=13.1, 8.1 Hz, 4H), 3.89-3.81(m, 4H), 7.16-7.07(m, 2H), 7.56(s, 1H), 7.58(s, 1H), 7.93-7.81(m, 1H), 8.18-8.10(m, 1H), 8.71-8.55(m, 1H), 9.17(s, 1H)。MS(ESI +)m/z 526.2(M+H) +。
Embodiment 174
6-(2,6-dichlorophenyl)-2-{[4-(2-oxo piperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 174A
4-(4-{[6-(2,6-dichlorophenyl)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } phenyl)-3-oxo piperazine-1-formic acid tertiary butyl ester
As described in embodiment 109A, prepare title compound (0.011 g), the alternative 7'-amino-1'H-spiral shell of use 4-(4-aminophenyl)-3-oxo piperazine-1-formic acid tertiary butyl ester [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-2'(3'H)-formic acid tertiary butyl ester.With Analogix 280 (SF 12-24 post), carry out chromatographic separation, use 50% to 100% ethyl acetate/hexane gradient elution 30 minutes, title compound is provided.MS(ESI +)m/z 621.4(M+H) +。
Embodiment 174B
6-(2,6-dichlorophenyl)-2-{[4-(2-oxo piperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 109B, prepare title compound (0.1g), with embodiment 174A alternate embodiment 109A.Tfa salt is dissolved in methyl alcohol, with excessive 2M HCl/ diethyl ether, processes, stir, until start to form solid.With ether, dilute this mixture, stir 10 minutes, filter, title compound is provided. 1H NMR(300 MHz, DMSO-d 6) δ 3.55(d, 2 H)3.90(d, 4 H)7.13(d, J=1.70 Hz, 1 H)7.38(d, J=8.82 Hz, 2 H)7.58-7.71(m, 1 H)7.73-7.80(m, 2 H)7.91(s, 3 H)9.19(s, 1 H)9.68(s, 2 H)10.96(s, 1 H)。MS(ESI +)m/z 521.3(M+H) +。
Embodiment 175
2-(4-[(1R, 4R) and-2,5-diazabicyclo [2.2.1] heptan-2-yl] phenyl } amino)-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 175A
(1R, 4R)-5-(4-{[6-(2,6-dichlorophenyl)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } phenyl)-2,5-diazabicyclo [2.2.1] heptane-2-formic acid tertiary butyl ester
As described in embodiment 109A, prepare title compound (0.11 g), with (1R, 4R)-5-(4-aminophenyl)-2,5-diazabicyclo [2.2.1] heptane-2-formic acid tertiary butyl ester substitutes 7'-amino-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-2'(3'H)-formic acid tertiary butyl ester.With Analogix 280 (SF 12-24 post), carry out chromatographic separation, use 40% to 100% ethyl acetate/hexane gradient elution 30 minutes.MS(ESI +)m/z 619.3(M+H) +。
Embodiment 175B
2-(4-[(1R, 4R) and-2,5-diazabicyclo [2.2.1] heptan-2-yl] phenyl } amino)-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 109B, prepare title compound (0.1g), with embodiment 175A alternate embodiment 109A.Tfa salt is dissolved in methyl alcohol, with excessive 2M HCl/ diethyl ether, processes, stir, until start to form solid.With ether, dilute this mixture, stir 10 minutes, filter, title compound is provided. 1H NMR(300 MHz, DMSO-d 6) δ 2.00(d, 2 H)3.22(d, 2 H)3.64(d, 2 H)4.44(d, 1 H)4.61(d, 1 H)6.75(d, J=8.72 Hz, 2 H)7.11(s, 1 H)7.41-7.93(m, 6 H)8.75(s, 1 H)9.09(s, 1 H)9.35(s, 1 H)10.70(s, 1 H)。MS(ESI +)m/z 519.2(M+H) +。
Embodiment 176
6-(2,6-dichlorophenyl)-2-{[4-(4-methylpiperazine-1-yl)-3-(third-2-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 150, prepare title compound (0.05 g), with 3-sec.-propyl-4-(4-methylpiperazine-1-yl) aniline, substitute 1,1,2-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-6-amine, purifies (on Phenomenex Luna C8 (2) 5 μ m 100 AXIA posts (30mm * 75mm)) with preparative HPLC.Use the gradient of acetonitrile (A) and 0.1% trifluoroacetic acid/water (B), flow velocity 50 mL/min (0-0.5 min, 10% A; 0.5-7.0 min linear gradient, 10-95% A; 7.0-10.0 min, 95% A; 10.0-12.0 min linear gradient, 95-10% A).Tfa salt is dissolved in methyl alcohol, with excessive 2M HCl/ diethyl ether, processes, stir, until start to form solid.With ether, dilute this mixture, stir 10 minutes, filter. 1H NMR(300 MHz, DMSO-d 6) δ 1.15-1.33(m, 6 H)2.73-2.94(m, 3 H)2.99-3.16(m, 4 H)3.16-3.30(m, 2 H)3.40-3.50(m, 2 H)6.96-7.37(m, 2 H)7.47-7.91(m, 6 H)9.15(s, 1 H)10.30(s, 1 H)10.80(s, 1 H)。MS(ESI +)m/z 526.2(M+H) +。
Embodiment 177
6-(2,6-dichlorophenyl)-2-[(1,1,2,3,3-pentamethyl--2,3-dihydro-1H-isoindole-5-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 150, prepare title compound (0.062 g), with 3-sec.-propyl-4-(4-methylpiperazine-1-yl) aniline, substitute 1,1,2-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-6-amine, purifies (on Phenomenex Luna C8 (2) 5 μ m 100 AXIA posts (30mm * 75mm)) with preparative HPLC.Use the gradient of acetonitrile (A) and 0.1% trifluoroacetic acid/water (B), flow velocity 50 mL/min (0-0.5 min, 10% A; 0.5-7.0 min linear gradient, 10-95% A; 7.0-10.0 min, 95% A; 10.0-12.0 min linear gradient, 95-10% A).Tfa salt is dissolved in methyl alcohol, with excessive 2M HCl/ diethyl ether, processes, stir, until start to form solid.With ether, dilute this mixture, stir 10 minutes, filter, title compound is provided. 1H NMR(300 MHz, DMSO-d 6) δ1.55(d, 6 H)1.82(d, 6 H)2.86(d, 3 H)7.14(d, J=1.98 Hz, 1 H)7.42-7.53(m, 1 H)7.58-7.69(m, 1 H)7.75(t, J=8.13 Hz, 4 H)7.82-7.98(m, 1 H)9.20(s, 1 H)9.96(d, J=3.97 Hz, 1 H)11.00(s, 1 H)。MS(ESI +)m/z 534.2(M+H) +。
Embodiment 178
6-(2,6-dichlorophenyl)-2-[(1,1,2-trimethylammonium-2,3-dihydro-1H-isoindole-5-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 150, prepare title compound (0.045 g), with 1,1,2-trimethylammonium isoindoline-5-amine substitutes 1,1,2-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-6-amine, purifies (on Phenomenex Luna C8 (2) 5 μ m 100 AXIA posts (30mm * 75mm)) with preparative HPLC.Use the gradient of acetonitrile (A) and 0.1% trifluoroacetic acid/water (B), flow velocity 50 mL/min (0-0.5 min, 10% A; 0.5-7.0 min linear gradient, 10-95% A; 7.0-10.0 min, 95% A; 10.0-12.0 min linear gradient, 95-10% A).Tfa salt is dissolved in methyl alcohol, with excessive 2M HCl/ diethyl ether, processes, stir, until start to form solid.With ether, dilute this mixture, stir 10 minutes, filter, title compound is provided. 1H NMR(300 MHz, DMSO-d 6) δ 1.27-1.54(m, 3 H)1.63-1.85(m, 3 H)2.81-3.00(m, 3 H)4.48-4.68(m, 1 H)4.68-4.86(m, 1 H)7.09-7.17(m, 1 H)7.45(d, J=8.48 Hz, 1 H)7.57-7.72(m, 1 H)7.71-7.81(m, 3 H)7.90(d, J=12.21 Hz, 2 H)9.20(s, 1 H)10.78(s, 1 H)11.00(s, 1 H)。MS(ESI +)m/z 506.0(M+H) +。
Embodiment 179
(3aS, 10aS)-8-{[6-(2,6-dichlorophenyl)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino }-2,3,3a, 5,10,10a-hexahydropyrrolo is [3,4-c] [1] benzo-aza also
Figure 86492DEST_PATH_IMAGE002
-4 (1H)-one
Embodiment 179A
(3aS, 10aS)-8-{[6-(2,6-dichlorophenyl)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino }-4-oxo-3,3a, 4,5,10,10a-hexahydropyrrolo is [3,4-c] [1] benzo-aza also
Figure 483975DEST_PATH_IMAGE002
-2 (1H)-formic acid tertiary butyl ester
As described in embodiment 109A, prepare title compound (0.1g), with (3aS, 10aS)-8-amino-4-oxo-3,3a, 4,5,10,10a-hexahydrobenzene is [b] pyrrolo-[3,4-e] azepine also -2 (1H)-formic acid tertiary butyl ester substitute 7'-amino-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-2'(3'H)-formic acid tertiary butyl ester.Crude product is ground together with ethyl acetate, title compound is provided.MS(ESI +)m/z 647.4(M+H) +。
Embodiment 179B
(3aS, 10aS)-8-{[6-(2,6-dichlorophenyl)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino }-2,3,3a, 5,10,10a-hexahydropyrrolo is [3,4-c] [1] benzo-aza also
Figure 291711DEST_PATH_IMAGE002
-4 (1H)-one
As described in embodiment 109B, prepare title compound (0.09g), with embodiment 179A alternate embodiment 109A.Tfa salt is dissolved in methyl alcohol, with excessive 2M HCl/ diethyl ether, processes, stir, until start to form solid.With ether, dilute this mixture, stir 10 minutes, filter, title compound is provided. 1H NMR(300 MHz, DMSO-d 6) δ 2.57-2.80(m, 1 H)2.81-3.17(m, 3 H)3.18-3.47(m, 2 H)3.46-3.66(m, 2 H)6.90-7.31(m, 2 H)7.42-8.03(m, 6 H)8.92-9.31(m, 3 H)9.92(s, 1 H)10.85(s, 1 H)。MS(ESI +)m/z 547.2(M+H) +。
Embodiment 180
6-(2,6-dichlorophenyl)-2-{[4-(6-oxo-Isosorbide-5-Nitrae, 5,6-tetrahydro pyridazine-3-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 150, prepare title compound (0.095 g), with 6-(4-aminophenyl)-4,5-dihydrogen dazin-3 (2H)-one substitutes 1,1,2-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-6-amine.Crude product is ground together with ethyl acetate, title compound is provided. 1H NMR(300 MHz, DMSO-d 6) δ 2.38-2.48(m, 2 H)2.97(t, J=8.13 Hz, 2 H)7.13(d, J=1.59 Hz, 1 H)7.45-8.12(m, 8 H)9.20(s, 1 H)10.90(s, 1 H)11.03(s, 1 H)。MS(ESI +)m/z 642.93(M+H) +。
Embodiment 181
2-(1,2,3-diazosulfide-5-base is amino)-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 150, prepare title compound (0.04 g), with benzo [d] [1,2,3] thiadiazoles-5-amine, substitute 1,1,2-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-6-amine.Crude product is ground together with ethyl acetate, title compound is provided. 1H NMR(500 MHz, DMSO-d 6) δ 7.17(d, J=1.53 Hz, 1 H)7.59-7.70(m, 1 H)7.78(d, J=8.24 Hz, 2 H)7.88(s, 1 H)8.08-8.32(m, 1 H)8.43(d, J=8.85 Hz, 1 H)9.27(d, J=20.75 Hz, 2 H)11.32(s, 1 H)。MS(ESI +)m/z 480.9(M+H) +。
Embodiment 182
2-(1,3-benzothiazol-6-yl is amino)-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 150, prepare title compound (0.035 g), with the chloro-4-of 3-(4-methylpiperazine-1-yl) aniline, substitute 1,1,2-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-6-amine.With Analogix 280 (SF 12-24 post), carry out chromatographic separation, use 50% to 100% ethyl acetate/hexane gradient elution 30 minutes. 1H NMR(300 MHz, DMSO-d 6) δ 7.14(d, J=1.98 Hz, 1 H)7.54-7.71(m, 1 H)7.70-7.84(m, 2 H)7.92(d, J=7.93 Hz, 2 H)8.12(d, J=8.73 Hz, 1 H)8.71(s, 1 H)9.22(s, 1 H)9.32(s, 1 H)11.11(s, 1 H)。MS(ESI +)m/z 480.1(M+H) +。
Embodiment 183
2-(4-[bis-(2-methoxy ethyl) amino] and phenyl } amino)-6-(2-chloro-phenyl-) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 183A
N, N-bis-(2-methoxy ethyl)-4-N-methyl-p-nitroaniline
By the fluoro-4-oil of mirbane of 1-(133 mg, 0.94 mmol), two (2-methoxy ethyl) amine (125 mg, 0.94 mmol) and salt of wormwood (143 mg, 1.04 mmol) in DMSO (2 mL), at 70 ℃, stir 24 hours.This reaction mixture is poured into water, and ethyl acetate for water (2 x 25 mL) is extracted.The organic extraction merging with salt water washing, by dried over mgso, filters, concentrated, and title compound is provided.MS(ESI +)m/e 255.1(M + H) +。
Embodiment 183B
N 1, N 1-bis-(2-methoxy ethyl) benzene-Isosorbide-5-Nitrae-diamines
In 10 mL rotating disc type pressure bottles (carousel pressure bottle), embodiment 183A (130 mg, 0.51 mmol)/ethanol (1.5 mL) is joined in 5% Pd/C (moistening, 13 mg).By this mixture under the hydrogen of 30 psi, at 50 ℃, stir 1 hour.By polypropylene screen, filter this mixture, concentrated, title compound is provided.MS(ESI +)m/e 225.1(M + H) +。
Embodiment 183C
2-(4-[bis-(2-methoxy ethyl) amino] and phenyl } amino)-6-(2-chloro-phenyl-) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
By embodiment 1E (40 mg, 0.11 mmol), embodiment 183B (25 mg, 0.11 mmol) and trifluoroacetic acid (1 μ L) in acetonitrile (3 mL), at room temperature stir 24 hours.Concentrated this reaction mixture.By RP-HPLC (Sunfire 50 X 250 mm, 5 μ M) this crude mixture of purifying, use the gradient elution of 10/90 acetonitrile/0.1% TFA-water to 50/50, through 30 minutes (254 nm), provide the tfa salt of title compound. 1H NMR(400 MHz, DMSO-d 6, 90o C) δ 10.14(br s, 1H), 9.01(s, 1H), 7.71(m, 1H), 7.65(m, 1H), 7.54(m, 5H), 7.02 s, 1H),, 6.79(br, d, 2H), 3.57(m, 8H), 3.29(s, 6H)。MS(ESI +)m/e 520.1(M + H) +。
Embodiment 184
6-(2-chloro-phenyl-)-2-[(3-cyclopropyl-2,3,4,5-tetrahydrochysene-1H-3-benzo-aza
Figure 602738DEST_PATH_IMAGE002
-7-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 130B, prepare title compound, with 3-cyclopropyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine
Figure 108806DEST_PATH_IMAGE002
-7-amine alternate embodiment 130A.Before HPLC, need not carry out aqueous solution processing. 1H NMR(400 MHz, CD 3OD)δ 1.19-1.00(m, 4H), 2.98-2.89(m, 1H), 3.39-3.04(m, 6H), 4.00-3.88(m, 2H), 7.06(d, J=1.9 Hz, 1H), 7.33-7.26(m, 1H), 7.63-7.53(m, 3H), 7.71-7.66(m, 3H), 7.84(s, 1H), 9.14(s, 1H)。MS(ESI +)m/z 498.2(M+H) +。
Embodiment 185
6-(2-chloro-phenyl-)-2-{[3-(2,2-, bis-fluoro ethyls)-2,3,4,5-tetrahydrochysene-1H-3-benzo-aza -7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 130B, prepare title compound, with 3-(2,2-, bis-fluoro ethyls)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine
Figure 269845DEST_PATH_IMAGE002
-7-amine alternate embodiment 130A.Before HPLC, need not carry out aqueous solution processing. 1H NMR(400 MHz, CD 3OD)δ 3.32-3.21(m, 5H), 3.67-3.50(bs, 4H), 3.84(td, J=14.7, 3.7 Hz, 2H), 7.06(d, J=1.9 Hz, 1H), 7.33-7.26(m, 1H), 7.62-7.53(m, 3H), 7.73-7.65(m, 3H), 7.84(d, J=0.7 Hz, 1H), 9.15(s, 1H)。MS(ESI +)m/z 522.2(M+H) +。
Embodiment 186
6-(2-chloro-4,6-difluorophenyl)-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 186A
4-(2-chloro-4,6-difluorophenyl)-8-methyl sulfenyl-4H-3,4,7,9,9b-pentaaza-cyclopenta [a] naphthalene-5-ketone
According to the described general method of embodiment 1A to embodiment 1D, prepare title compound, in embodiment 1A, chloro-3 with 1-, the fluoro-2-isocyanato of 5-bis-benzene substitutes the chloro-2-isocyanato of 1-benzene, and reduces the reaction times (2 hours).Ordinary skill is used for changing reactant aftertreatment and purification process.Change to embodiment 1A: during processing, water layer acidifying, and be settled out product.Change to embodiment 1B: purification of target product on silica column, use ISCO Companion flash chromatographic system, use CH 2cl 2/ hexane (90:10 to 95:5) wash-out.Change to embodiment 1D: grind together with ethyl acetate, separate targets product, then uses NaHCO 3the aqueous solution and diethyl ether washing.
Embodiment 186B
6-(2-chloro-4,6-difluorophenyl)-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 123B, prepare title compound, with embodiment 186A alternate embodiment 123A. 1H NMR(400 MHz, CD 3OD)δ 2.98(s, 3H), 3.19-3.00(m, 2H), 3.33-3.27(m, 2H), 3.67-3.59(m, 2H), 3.89-3.82(m, 2H), 7.13-7.03(m, 3H), 7.33(td, J=9.1, 2.8 Hz, 1H), 7.44(dt, J=8.3, 2.2 Hz, 1H), 7.94-7.62(m, 3H), 9.14-9.08(m, 1H)。MS(ESI +)m/z 523.2(M+H) +。
Embodiment 187
6-(2-chloro-4,6-difluorophenyl)-2-[(2,4,4-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-7-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 123B, prepare title compound, with embodiment 186A and 2,4,4-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-7-amine is alternate embodiment 123A and 4-(4-methylpiperazine-1-yl) aniline respectively. 1H NMR(400 MHz, CD 3OD)δ 1.48(s, 6H), 3.12(s, 3H), 3.43-3.30(m, 1H), 3.67-3.45(m, 1H), 4.63-4.38(m, 2H), 7.10(d, J=1.8 Hz, 1H), 7.38-7.27(m, 1H), 7.49-7.41(m, 1H), 7.57(d, J=8.2 Hz, 1H), 7.82-7.68(m, 2H), 7.89(d, J=1.5 Hz, 1H), 9.18(s, 1H)。MS(ESI +)m/z 522.1(M+H) +。
Embodiment 188
6-(2-chloro-4,6-difluorophenyl)-2-{[2-(dimethylamino)-2,3-dihydro-1H-indenes-5-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 123B, prepare title compound, with embodiment 186A and N 2, N 2-dimethyl-2,3-dihydro-1H-indenes-2,5-diamines is alternate embodiment 123A and 4-(4-methylpiperazine-1-yl) aniline respectively. 1H NMR(400 MHz, CD 3OD)δ 2.96(s, 6H), 3.32-3.18(m, 2H), 3.56-3.40(m, 2H), 4.22-4.14(m, 1H), 7.08(d, J=1.9 Hz, 1H), 7.37-7.28(m, 2H), 7.46-7.43(m, 1H), 7.60(bs, 1H), 7.87-7.77(m, 2H), 9.13(s, 1H)。MS(ESI +)m/z 508.1(M+H) +。
Embodiment 189
6-(2-chloro-phenyl-)-2-[(4-{[3-(morpholine-4-yl) propyl group] amino } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 189A
N-(3-morpholino propyl group)-4-N-methyl-p-nitroaniline
As described in embodiment 183A, prepare title compound, with N-(3-aminopropyl) morpholine, substitute two (2-methoxy ethyl) amine.MS(ESI +)m/e 266.1(M + H) +。
Embodiment 189B
N 1-(3-morpholino propyl group) benzene-Isosorbide-5-Nitrae-diamines
As described in embodiment 183B, prepare title compound, with embodiment 189A alternate embodiment 183A.MS(ESI +)m/e 236.2(M + H) +。
Embodiment 189C
6-(2-chloro-phenyl-)-2-[(4-{[3-(morpholine-4-yl) propyl group] amino } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 183C, prepare title compound, with embodiment 189B alternate embodiment 183B. 1H NMR(400 MHz, DMSO-d 6, 90 o C) δ 10.11(s, 1H), 9.01(s, 1H), 7.67(m, 2H), 7.53(m, 5H), 7.02(s, 1H), 6.68(d, 2H), 3.84(m, 4H), 3.24(m, 4H), 3.18(m, 4H), 1.98(m, 2H)。MS(ESI +)m/e 531.2(M + H) +。
Embodiment 190
6-(2-chloro-phenyl-)-2-(4-[4-(pyrrolidin-1-yl) piperidin-1-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 190A
1-(4-nitrophenyl)-4-(pyrrolidin-1-yl) piperidines
As described in embodiment 183A, prepare title compound, with 4-(1-pyrrolidyl) piperidines, substitute two (2-methoxy ethyl) amine.MS(ESI +)m/e 276.1(M + H) +。
Embodiment 190B
4-(4-(pyrrolidin-1-yl) piperidin-1-yl) aniline
As described in embodiment 183B, prepare title compound, with embodiment 190A alternate embodiment 183A.MS(ESI +)m/e 236.2(M + H) +。
Embodiment 190C
6-(2-chloro-phenyl-)-2-(4-[4-(pyrrolidin-1-yl) piperidin-1-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 183C, prepare title compound, with embodiment 190B alternate embodiment 183B. 1H NMR(400 MHz, DMSO-d 6, 90o C) δ 10.25(br s, 1H), 9.05(s, 1H), 7.60(m, 5H), 7.41(m, 1H), 7.05(m, 4H), 3.92(m, 1H), 3.80(br d, 2H), 2.81(m, 3H), 1.93(m, 11H)。MS(ESI +)m/e 541.2(M + H) +。
Embodiment 191
6-(2-chloro-phenyl-)-2-(4-[4-(dimethylamino) piperidin-1-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 191A
N, N-dimethyl-1-(4-nitrophenyl) piperidines-4-amine
As described in embodiment 183A, prepare title compound, with 4-(dimethylamino) piperidines, substitute two (2-methoxy ethyl) amine.MS(ESI +)m/e 250.1(M + H) +。
Embodiment 191B
1-(4-aminophenyl)-N, N-lupetidine-4-amine
As described in embodiment 183B, prepare title compound, with embodiment 191A alternate embodiment 183A.MS(ESI +)m/e 220.1(M + H) +。
Embodiment 191C
6-(2-chloro-phenyl-)-2-(4-[4-(dimethylamino) piperidin-1-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 183C, prepare title compound, with embodiment 191B alternate embodiment 183B. 1H NMR(400 MHz, DMSO-d 6, 90o C) δ 10.25(s, 1H), 9.05(s, 1H), 7.66(m, 4H), 7.54(m, 3H), 7.03(m, 3H), 3.64(m, 2H), 3.32(m, 2H), 2.81(s, 6H), 2.77(m, 1H), 2.10(m, 2H), 1.76(m, 2H)。MS(ESI +)m/e 515.1(M + H) +。
Embodiment 192
6-(2-chloro-phenyl-)-2-[(4-{[2-(1-methylpyrrolidin-2-yl) ethyl] amino } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 192A
N-(2-(1-methylpyrrolidin-2-yl) ethyl)-4-N-methyl-p-nitroaniline
As described in embodiment 183A, prepare title compound, with 2-(2-amino-ethyl)-1-crassitude, substitute two (2-2-methoxy ethyl) amine.MS(ESI +)m/e 250.2(M + H) +。
Embodiment 192B
N 1-(2-(1-methylpyrrolidin-2-yl) ethyl) benzene-Isosorbide-5-Nitrae-diamines
As described in embodiment 183B, prepare title compound, with embodiment 192A alternate embodiment 183A.MS(ESI +)m/e 220.2(M + H) +。
Embodiment 192C
6-(2-chloro-phenyl-)-2-[(4-{[2-(1-methylpyrrolidin-2-yl) ethyl] amino } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 183C, prepare title compound, with embodiment 192B alternate embodiment 183B. 1H NMR(400 MHz, DMSO-d 6, 90o C) δ 10.11(br s, 1H), 9.01(s, 1H), 7.67(m, 2H), 7.53(m, 5H), 7.01 (m, 1H), 6.68(m, 2H), 3.18(m, 5H), 2.82(s, 3H), 2.32(m, 1H), 2.16(m, 1H), 1.99(m, 2H), 1.80(m, 2H)。MS(ESI +)m/e 515.2(M + H) +。
Embodiment 193
4-{[6-(2,6-dichlorophenyl)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } phenylformic acid 4-(dimethylamino) cyclohexyl ester
As described in embodiment 150, prepare title compound (0.05 g), with PABA 4-(dimethylamino) cyclohexyl ester HCl salt, substitute 1,1,2-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-6-amine, purifies (on Phenomenex Luna C8 (2) 5 μ m 100 AXIA posts (30mm * 75mm)) with preparative HPLC.Use the gradient of acetonitrile (A) and 0.1% trifluoroacetic acid/water (B), flow velocity 50 mL/min (0-0.5 min, 10% A; 0.5-7.0 min linear gradient, 10-95% A; 7.0-10.0 min, 95% A; 10.0-12.0 min linear gradient, 95-10% A).Tfa salt is dissolved in methyl alcohol, with excessive 2M HCl/ diethyl ether, processes, stir, until start to form solid.With ether, dilute this mixture, stir 10 minutes, filter, title compound is provided. 1H NMR(300 MHz, DMSO-d 6) δ 1.85(t, 8 H)2.73(t, 6 H)3.23(t, 1 H)7.15(t, J=1.98 Hz, 1 H)7.58-7.70(m, 1 H)7.73-7.81(m, 2 H)7.87-8.29(m, 5 H)9.11-9.45(m, 1 H)10.11(s, 1 H)11.21(s, 1 H)。MS(ESI +)m/z 591.2(M+H) +。
Embodiment 194
6-(2,6-dichlorophenyl)-2-(1H-indazole-5-base is amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 109A, prepare title compound (0.095 g), the alternative 7'-amino-1'H-spiral shell of use 5-amino-1 h-indazole-1-formic acid tertiary butyl ester [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-2'(3'H)-formic acid tertiary butyl ester.With Analogix 280 (SF 12-24 post), carry out chromatographic separation, use 50% to 100% ethyl acetate/hexane gradient elution 30 minutes.Crude product compound is dissolved in methylene dichloride, and processes with excessive TFA.This mixture is stirred 30 minutes, concentrated.Tfa salt is dissolved in methyl alcohol, with 2M HCl/ diethyl ether, processes 30 minutes, with ether dilution, filter high vacuum dry. 1H NMR(300 MHz, DMSO-d 6) δ 7.12(d, J=1.98 Hz, 1 H)7.36-8.02(m, 6 H)7.99-8.48(m, 2 H)9.16(s, 1 H)10.92(s, 1 H)。MS(ESI +)m/z 463.1(M+H) +。
Embodiment 195
6-(2,6-dichlorophenyl)-2-(4-[(3S) and-3-(third-2-yl) piperazine-1-yl] phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 195A
(2S)-4-(4-{[6-(2,6-dichlorophenyl)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } phenyl)-2-(third-2-yl) piperazine-1-formic acid tertiary butyl ester
As described in embodiment 109A, prepare title compound (0.06 g), by (S)-4-(4-aminophenyl)-2-sec.-propyl piperazine-1-formic acid tertiary butyl ester, substitute 7'-amino-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-2'(3'H)-formic acid tertiary butyl ester.With Analogix 280 (SF 12-24 post), carry out chromatographic separation, use 50% to 100% ethyl acetate/hexane gradient elution 30 minutes, obtain yellow (yellow fil), title compound is provided.MS(ESI +)m/z 649.27(M+H) +。
Embodiment 195B
6-(2,6-dichlorophenyl)-2-(4-[(3S) and-3-(third-2-yl) piperazine-1-yl] phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 109B, prepare title compound (0.05g), with embodiment 195A alternate embodiment 109A.Tfa salt is dissolved in methyl alcohol, with excessive 2M HCl/ diethyl ether, processes, stir, until start to form solid.With ether, dilute this mixture, stir 10 minutes, filter, title compound is provided. 1H NMR(300 MHz, DMSO-d 6) δ 0.95-1.20(m, 6 H)1.85-2.13(m, 1 H)2.66-3.27(m, 4 H)3.25-3.46(m, 1 H)3.77(d, J=13.09 Hz, 2 H)7.12(d, J=1.59 Hz, 3 H)7.36-8.04(m, 6 H)9.12(s, 3 H)10.78(s, 1 H)。MS(ESI +)m/z 549.2(M+H) +。
Embodiment 196
6-(2,6-dichlorophenyl)-2-[(4-{1-[1-(dimethylamino)-3-methyl butyl] cyclobutyl } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 150, prepare title compound (0.06 g), with 4-(1-(1-(dimethylamino)-3-methyl butyl) cyclobutyl) aniline, substitute 1,1,2-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-6-amine.With Analogix 280 (SF 12-24 post), carry out chromatographic separation, use 10% ethanol/methylene gradient elution 40 minutes.Crude product is dissolved in methyl alcohol, and processes with 2M HCl/ diethyl ether, filter, title compound is provided. 1H NMR(300 MHz, DMSO-d 6) δ 1.01(t, J=5.75 Hz, 6 H)1.27-1.56(m, 2 H)1.60-2.03(m, 3 H)2.15(d, J=4.76 Hz, 3 H)2.34(t, J=7.34 Hz, 2 H)2.61(t, J=7.74 Hz, 2 H)2.73-2.88(m, 3 H)3.75(t, J=5.75 Hz, 1 H)7.14(s, 1 H)7.47-7.70(m, 3 H)7.71-7.82(m, 2 H)7.92(d, J=1.59 Hz, 3 H)9.00(s, 1 H)9.20(s, 1 H)10.98(s, 1 H)。MS(ESI +)m/z 589.9(M+H) +。
Embodiment 197
6-(2,6-dichlorophenyl)-2-(4-[4-methyl-2-(methylamino)-1,3-thiazoles-5-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 150, prepare title compound (0.09 g), with 5-(4-aminophenyl)-N, 4-dimethylthiazole-2-amine substitutes 1,1,2-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-6-amine.Crude product is ground together with methylene dichloride, title compound is provided. 1H NMR(300 MHz, DMSO-d 6) δ 2.19-2.31(m, 3 H)2.71-2.91(m, 3 H)7.12(d, J=1.59 Hz, 1 H)7.33-7.53(m, 3 H)7.58-7.69(m, 1 H)7.72-7.80(m, 2 H)7.89(s, 3 H)9.18(s, 1 H)10.94(s, 1 H)。MS(ESI +)m/z 549.1(M+H) +。
Embodiment 198
6-(2,6-dichlorophenyl)-2-{[6-(piperazine-1-yl) pyridin-3-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 198A
4-(5-{[6-(2,6-dichlorophenyl)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } pyridine-2-yl) piperazine-1-formic acid tertiary butyl ester
As described in embodiment 109A, prepare title compound (0.095 g), the alternative 7'-amino-1'H-spiral shell of use 4-(5-aminopyridine-2-yl) piperazine-1-formic acid tertiary butyl ester [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-2'(3'H)-formic acid tertiary butyl ester.With Analogix 280 (SF 12-24 post), carry out chromatographic separation, use 40% to 100% ethyl acetate/hexane gradient elution 30 minutes, title compound is provided.MS(ESI+)m/z 608.31(M+H)+。
Embodiment 198B
6-(2,6-dichlorophenyl)-2-{[6-(piperazine-1-yl) pyridin-3-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 109B, prepare title compound (0.09g), with embodiment 198A alternate embodiment 109A.Tfa salt is dissolved in methyl alcohol, with excessive 2M HCl/ diethyl ether, processes, stir, until start to form solid.With ether, dilute this mixture, stir 10 minutes, filter, title compound is provided. 1H NMR(300 MHz, DMSO-d 6) δ 2.93-3.47(m, 4 H)3.82(s, 4 H)6.89-7.36(m, 2 H)7.43-8.00(m, 5 H)8.17(s, 1 H)8.73(s, 1 H)8.98-9.47(m, J=32.13 Hz, 3 H)10.93(s, 1 H)。MS(ESI +)m/z 508.1(M+H) +。
Embodiment 199
6-(2,6-dichlorophenyl)-2-(1H-indazole-6-base is amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 199A
6-{[6-(2,6-dichlorophenyl)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino }-1H-indazole-1-formic acid tertiary butyl ester
As described in embodiment 109A, prepare title compound (0.08 g), the alternative 7'-amino-1'H-spiral shell of use 6-amino-1 h-indazole-1-formic acid tertiary butyl ester [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-2'(3'H)-formic acid tertiary butyl ester.With Analogix 280 (SF 12-24 post), carry out chromatographic separation, use 40% to 100% ethyl acetate/hexane gradient elution 30 minutes, title compound is provided.MS(ESI +)m/z 563.2(M+H) +。
Embodiment 199B
6-(2,6-dichlorophenyl)-2-(1H-indazole-6-base is amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 109B, prepare title compound (0.08g), with embodiment 199A alternate embodiment 109A.Tfa salt is dissolved in methyl alcohol, with excessive 2M HCl/ diethyl ether, processes, stir, until start to form solid.With ether, dilute this mixture, stir 10 minutes, filter, title compound is provided. 1H NMR(300 MHz, DMSO-d 6) δ 7.19(s, 1 H)7.43(dd, J=8.92, 1.78 Hz, 1 H)7.57-7.70(m, 1 H)7.71-7.82(m, 3 H)7.88-8.13(m, 2 H)8.47(s, 1 H)9.21(s, 1 H)11.07(s, 1 H)。MS(ESI +)m/z 463.1(M+H) +。
Embodiment 200
4-{[6-(2,6-dichlorophenyl)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } phenylformic acid (1R)-octahydro-2H-quinolizine-1-base ester
As described in embodiment 150, prepare title compound (0.055 g), with PABA (1R)-octahydro-1H-quinolizine-1-base ester HCl salt, substitute 1,1,2-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-6-amine, with Analogix 280 (SF 12-24 post) purifying, 0% to 6% ethanol/methylene gradient elution 30 minutes.Crude product is dissolved in methyl alcohol, and processes 20 minutes with 2M HCl/ diethyl ether, filter, title compound is provided. 1H NMR(300 MHz, DMSO-d 6) δ 1.35-2.12(m, 10 H)2.10-2.33(m, 1 H)2.88-3.13(m, 2 H)3.41-3.53(m, 2 H)4.87-5.13(m, 1 H)7.15(d, J=1.70 Hz, 1 H)7.59-7.71(m, 1 H)7.73-7.81(m, 2 H)8.06(s, 4 H)9.25(s, 1 H)10.36(s, 1 H)11.23(s, 1 H)。MS(ESI +)m/z 604.2(M+H) +。
Embodiment 201
4-{[6-(2,6-dichlorophenyl)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } phenylformic acid 2-[cyclopropyl (methyl) amino] ethyl ester
As described in embodiment 150, prepare title compound (0.055 g), with PABA 2-(cyclopropyl (methyl) amino) ethyl ester, substitute 1,1,2-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-6-amine, with Analogix 280 (SF 12-24 post) purifying, 0% to 7% ethanol/methylene gradient elution 30 minutes.Crude product is dissolved in methyl alcohol, and processes 20 minutes with 2M HCl/ diethyl ether, filter, title compound is provided. 1H NMR(300 MHz, DMSO-d 6) δ 0.69-1.23(m, 4 H)2.83-3.12(m, 4 H)3.55-3.81(m, 2 H)4.55-4.77(m, 2 H)7.16(s, 1 H)7.49-7.88(m, 3 H)7.88-8.27(m, 5 H)9.26(s, 1 H)10.09(s, 1 H)11.23(s, 1 H)。MS(ESI +)m/z 564.0(M+H) +。
Embodiment 202
6-(2,6-dichlorophenyl)-2-[(4-{[(1R, 5S)-7-ethyl-3,7-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-3-yl] carbonyl } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 150, prepare title compound (0.065 g), with (4-aminophenyl) ((1R, 5S)-7-ethyl-3,7-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-3-yl) ketone alternative 1,1,2-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-6-amine, with Analogix 280 (SF 12-24 post) purifying, 0% to 7% ethanol/methylene gradient elution 30 minutes.Crude product is dissolved in methyl alcohol, and processes 20 minutes with 2M HCl/ diethyl ether, filter, title compound is provided. 1H NMR(300 MHz, DMSO-d 6) δ 1.20-1.39(m, 3 H)1.60-1.98(m, 2 H)2.12-2.41(m, 2 H)3.14(d, 7 H)3.68(d, 2 H)4.03(d, 2 H)7.15(d, J=1.59 Hz, 1 H)7.32-8.11(m, 7 H)8.30(d, J=11.50 Hz, 1 H)9.22(s, 1 H)11.08(s, 1 H)。MS(ESI +)m/z 603.1(M+H) +。
Embodiment 203
6-(2-chloro-phenyl-)-2-{[3, the fluoro-4-of 5-bis-(piperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 203A
4-(the fluoro-4-nitrophenyl of 2,6-bis-) piperazine-1-formic acid tertiary butyl ester
As described in embodiment 183A, prepare title compound, with 3,4,5-trifluoronitrobenzene, substitute the fluoro-4-oil of mirbane of 1-, 1-boc-piperazine substitutes two (2-methoxy ethyl) amine.MS(ESI +)m/e 344.1(M + H) +。
Embodiment 203B
4-(4-amino-2,6-difluorophenyl) piperazine-1-formic acid tertiary butyl ester
As described in embodiment 183B, prepare title compound, with embodiment 203A alternate embodiment 183A.MS(ESI +)m/e 314.1(M + H) +。
Embodiment 203C
6-(2-chloro-phenyl-)-2-{[3, the fluoro-4-of 5-bis-(piperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
By embodiment 1E (40 mg, 0.11 mmol) and embodiment 203B (41 mg, 0.13 mmol) in acetonitrile (3 mL), at room temperature stir 24 hours.Concentrated this reaction mixture, and be dissolved in the 4 mL TFA of 1: 1: in methylene dichloride.After 18 hours, concentrated this reaction, with RP-HPLC (Sunfire 50 X 250 mm, 5 μ M) purifying, is used the gradient elution 30 minutes (254 nm) of 5/95 acetonitrile/0.1% TFA-water to 50/50, and the tfa salt of title compound is provided. 1H NMR(400 MHz, DMSO-d 6, 90o C) δ 10.67(s, 1H), 9.16(s, 1H), 7.67(m, 2H), 7.57(m, 5H), 7.07(s, 1H), 3.32(m, 4H), 3.22(m, 4H)。MS(ESI +)m/e 509.1(M + H) +。
Embodiment 204
6-(2-chloro-phenyl-)-2-({ 4-[(8aR)-hexahydropyrrolo is [1,2-a] pyrazine-2 (1H)-yl also] phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 204A
(R)-2-(4-nitrophenyl) octahydro pyrrolo-[1,2-a] pyrazine
As described in embodiment 183A, prepare title compound, with (R)-Isosorbide-5-Nitrae-diazabicyclo [4.3.0] nonane, substitute two (2-methoxy ethyl) amine.MS(ESI +)m/e 248.2(M + H) +。
Embodiment 204B
(R)-4-(hexahydropyrrolo is [1,2-a] pyrazine-2 (1H)-yl also) aniline
As described in embodiment 183B, prepare title compound, with embodiment 204A alternate embodiment 183A.MS(ESI +)m/e 218.0(M + H) +。
Embodiment 204C
6-(2-chloro-phenyl-)-2-({ 4-[(8aR)-hexahydropyrrolo is [1,2-a] pyrazine-2 (1H)-yl also] phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 183C, prepare title compound, with embodiment 204B alternate embodiment 183B. 1H NMR(400 MHz, DMSO-d 6, 90o C) δ 10.28(s, 1H), 9.05(s, 1H), 7.70(m, 4H), 7.55(m, 3H), 7.04(m, 3H), 3.50(m, 9H), 2.19(m, 1H), 2.06(m, 2H), 1.85(m, 1H)。MS(ESI +)m/e 513.2(M + H) +。
Embodiment 205
2-(2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-base amino)-6-(4-hydroxy phenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 205A
3-(4-(allyloxy) phenyl)-7-(methylthio group) Kui Linpyrimido quinoline [4,5-d] pyrimidine-2,4 (1H, 3H)-diketone
As described in embodiment 1A, prepare title compound (0.95 g), with 1-(allyloxy)-4-isocyanato benzene, substitute the chloro-2-isocyanato of 1-benzene.This solid matter through aftertreatment is filtered, title compound is provided.MS(ESI +)m/z 343.2(M+H) +。
Embodiment 205B
3-(4-(allyloxy) phenyl) the chloro-7-of-2-(methylthio group) Kui Linpyrimido quinoline [4,5-d] pyrimidine-4 (3H)-one
As described in embodiment 1B, prepare title compound (0.97 g), with embodiment 205A alternate embodiment 1A.MS(ESI +)m/z 361.19(M+H) +。
Embodiment 205C
3-(4-(allyloxy) phenyl)-2-(2,2-dimethoxy-ethyl is amino)-7-(methylthio group) Kui Linpyrimido quinoline [4,5-d] pyrimidine-4 (3H)-one
As described in embodiment 1C, prepare title compound (1 g), with embodiment 205B alternate embodiment 1B.MS(ESI +)m/z 430.28(M+H) +。
Embodiment 205D
2-(methyl sulfenyl)-6-[4-(third-2-alkene-1-base oxygen base) phenyl] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 1D, prepare title compound (0.975g), with embodiment 205C alternate embodiment 1C.MS(ESI +)m/z 366.1(M+H) +。
Embodiment 205E
2-(methylsulfinyl)-6-[4-(third-2-alkene-1-base oxygen base) phenyl] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 1E, prepare title compound (0.95g), with embodiment 205D alternate embodiment 1D.MS(ESI +)m/z 382.2(M+H) +。
Embodiment 205F
7'-(5-oxo-6-[4-(third-2-alkene-1-base oxygen base) phenyl]-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also } amino)-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-2'(3'H)-formic acid tertiary butyl ester
To adding 7'-amino-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-2'(3'H in the 4 mL acetonitrile solutions of embodiment 205E (125 mg, 0.328 mmol))-formic acid tertiary butyl ester (108 mg, 0.393 mmol).This reaction is heated to 60 ℃ and spends the night, cooling, with ethyl acetate dilution, use saturated NaHCO 3the aqueous solution, water and salt water washing, use MgSO 4dry, filter, concentrated.With Analogix 280 (SF 24-40 post) chromatogram purification crude product, with 20% to 100% ethyl acetate/hexane gradient elution 30 minutes, provide title compound.MS(ESI +)m/z 592.36(M+H) +。
Embodiment 205G
2-(2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-base amino)-6-(4-hydroxy phenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 54G, prepare title compound (0.035 g), with embodiment 205F alternate embodiment 54F.Use preparative HPLC purifying crude product (on Phenomenex Luna C8 (2) 5 μ m 100 AXIA posts (30mm * 75mm)).Use the gradient of acetonitrile (A) and 0.1% trifluoroacetic acid/water (B), flow velocity 50 mL/min (0-0.5 min, 10% A; 0.5-7.0 min linear gradient, 10-95% A; 7.0-10.0 min, 95% A; 10.0-12.0 min linear gradient, 95-10% A).Tfa salt is dissolved in methyl alcohol, with excessive 2M HCl/ diethyl ether, processes, stir, until start to form solid.With ether, dilute this mixture, stir 10 minutes, filter, title compound is provided. 1H NMR(300 MHz, DMSO-d 6) δ 1.11(s, 4 H)3.19-3.34(m, 2 H)4.45(s, 2 H)6.90(t, J=9.32 Hz, 3 H)7.08(d, J=1.98 Hz, 1 H)7.20(d, J=8.72 Hz, 2 H)7.49-7.98(m, 3 H)9.09(s, 1 H)9.42(s, 2 H)10.71(s, 1 H)。MS(ESI +)m/z 542.1(M+H) +。
Embodiment 206
6-(2,6-dichlorophenyl)-2-{[2'-(methylsulfonyl)-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl] amino imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
In the 2 mL DMF solution of embodiment 109B (75 mg, 0.149 mmol), add diisopropylethylamine (0.130 mL, 0.744 mmol), then add methylsulfonyl chloride (0.017 mL, 0.223 mmol).This reaction mixture is at room temperature stirred and spent the night, then by ethyl acetate, dilute.Use saturated NaHCO 3the aqueous solution, water and salt water washing organism, use MgSO 4dry, filter, concentrated.Crude product is ground together with ethyl acetate, filter, high vacuum dry, provides title compound. 1H NMR(300 MHz, DMSO-d 6) δ 0.85-1.12(m, 4 H)1.99(s, 2 H)2.86-3.02(m, 3 H)4.55(s, 2 H)6.90(d, J=8.33 Hz, 1 H)7.13(d, J=1.59 Hz, 1 H)7.44-7.94(m, 6 H)9.16(s, 1 H)10.84(s, 1 H)。MS(ESI +)m/z 582.1(M+H) +。
Embodiment 207
2-[(2'-ethanoyl-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl) amino]-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
In the 5 mL DMF solution of embodiment 109B (200 mg, 0.397 mmol), add diisopropylethylamine (0.346 mL, 1.983 mmol), then add diacetyl oxide (0.041 mL, 0.436 mmol).This reaction mixture is at room temperature stirred and spent the night, then by ethyl acetate, dilute.Use saturated NaHCO 3the aqueous solution, water and salt water washing organism, use MgSO 4dry, filter, concentrated.With Analogix 280 (SF 25-40 post) chromatogram purification crude product, with 0% to 4% ethanol/methylene gradient elution 30 minutes, provide title compound. 1H NMR(300 MHz, DMSO-d 6) δ 1.02(d, J=8.14 Hz, 4 H)2.10(d, J=21.70 Hz, 3 H)3.46-3.64(m, 2 H)4.75(s, 2 H)6.75-7.04(m, 1 H)7.12(s, 1 H)7.44-7.90(m, 6 H)9.16(s, 1 H)10.80(s, 1 H)。MS(ESI +)m/z 546.2(M+H) +。
Embodiment 208
6-(2-chloro-phenyl-)-2-{[4-(octahydro-2H-pyrido [1,2-a] pyrazine-2-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 208A
2-(4-nitrophenyl) octahydro-1H-pyrido [1,2-a] pyrazine
As described in embodiment 183A, prepare title compound, with (+/-)-Isosorbide-5-Nitrae-diazabicyclo [4.4.0] decane, substitute two (2-methoxy ethyl) amine.MS(ESI +)m/e 262.2(M + H) +。
Embodiment 208B
4-(dihydro-1H-pyrido [1,2-a] pyrazine-2 (6H, 7H, 8H, 9H, 9aH)-yl) aniline
As described in embodiment 183B, prepare title compound, with embodiment 208A alternate embodiment 183A.MS(ESI +)m/e 232.1(M + H) +。
Embodiment 208C
6-(2-chloro-phenyl-)-2-{[4-(octahydro-2H-pyrido [1,2-a] pyrazine-2-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 183C, prepare title compound, with embodiment 208B alternate embodiment 183B. 1H NMR(400 MHz, DMSO-d 6, 90o C) δ 10.29(s, 1H), 9.05(s, 1H), 7.68(m, 4H), 7.54(m, 3H), 7.05(m, 3H), 3.81(m, 2H), 3.45(m, 4H), 3.02(m, 2H), 2.65(m, 1H), 1.85(m, 4H), 1.56(m, 2H)。MS(ESI +)m/e 527.2(M + H) +。
Embodiment 209
6-(the chloro-6-fluorophenyl of 2-)-2-[(1,1,2-trimethylammonium-2,3-dihydro-1H-isoindole-5-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 123B, prepare title compound, with embodiment 95C and 1,1,2-trimethylammonium isoindoline-5-amine difference alternate embodiment 123A and 4-(4-methylpiperazine-1-yl) aniline.Carry out aqueous solution processing, then carry out HPLC purifying, title compound is provided. 1H NMR(400 MHz, CD 3OD)δ 1.55(s, 3H), 1.80(s, 3H), 3.03(s, 3H), 4.90-4.77(m, 1H), 4.66-4.57(m, 1H), 7.09(d, J=1.9 Hz, 1H), 7.50-7.30(m, 2H), 7.56-7.48(m, 1H), 7.63(td, J=8.4, 5.8 Hz, 1H), 7.80(bs, 1H), 7.90(d, J=1.9 Hz, 1H), 8.00(s, 1H), 9.20(s, 1H)。MS(ESI +)m/z 490.1(M+H) +。
Embodiment 210
6-(the chloro-6-fluorophenyl of 2-)-2-[(1,1,2,3,3-pentamethyl--2,3-dihydro-1H-isoindole-5-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 123B, prepare title compound, with embodiment 95C and 1,1,2,3,3-pentamethyl-isoindoline-5-amine difference alternate embodiment 123A and 4-(4-methylpiperazine-1-yl) aniline.Carry out aqueous solution processing, then carry out HPLC purifying, title compound is provided. 1H NMR(400 MHz, CD 3OD)δ 1.67(s, 3H), 1.70(s, 3H), 1.85(s, 3H), 1.88(s, 3H), 2.98(s, 3H), 7.10(d, J=1.9 Hz, 1H), 7.42-7.32(m, 1H), 7.49-7.42(m, 1H), 7.57-7.50(m, 1H), 7.63(td, J=8.4, 5.8 Hz, 1H), 7.87(bs, 2H), 9.22(s, 1H)。MS(ESI +)m/z 518.1(M+H) +。
Embodiment 211
6-(2-chloro-phenyl-)-2-(4-[4-(trimethylene oxide-3-yl) piperazine-1-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 211A
4-(piperazine-1-yl) phenylcarbamic acid benzyl ester
To 4-(4-aminophenyl) piperazine-1-formic acid tertiary butyl ester, (2.1 g add K in 7.6 mmol) diox (20 mL) solution 2cO 3(1.1 g, 8 mmol), then add benzyl chloroformate (carbonochloridate, 1.38 mL, 9.0 mmol).This mixture is at room temperature stirred 10 minutes.This reaction of water cancellation, and extract by ethyl acetate.Organic phase is concentrated, and be dissolved in CH 2cl 2in (20 ml), then add trifluoroacetic acid (2 ml).This mixture is at room temperature stirred and spent the night.Concentrated this reaction, by purification by flash chromatography (10% ethanol/methylene), provides title compound.MS(DCI/NH 3)m/z 312(M+H) +。
Embodiment 211B
4-(4-(trimethylene oxide-3-yl) piperazine-1-yl) aniline
In methyl alcohol (20 mL) solution of embodiment 211A (1.0 g, 3.21 mmol), add trimethylene oxide-3-ketone (278 mg, 3.8 mmol), and this mixture is stirred 3 hours at 50 ℃.Use NaCNBH 3(248 mg, 4.0 mmol) process this reaction mixture, and at 50 ℃, stir three days.This reaction mixture of water cancellation, and extract by ethyl acetate.Concentrated organic phase, and be dissolved in trifluoroacetic acid (2 ml).This mixture is spent the night 50 ℃ of stirrings.With flash chromatography (20% ethanol/methylene) purifying resistates, provide title compound. 1H NMR(300 MHz, CD 3OD) δ 2.41-2.57(m, 4 H), 2.98-3.09(m, 4 H), 3.47-3.65(m, 1 H), 4.62(t, J=6.27 Hz, 2 H), 4.70(q, J=6.33 Hz, 2 H), 6.64-6.75(m, 2 H), 6.77-6.90(m, 2 H)。MS(DCI/NH 3)m/z 234(M+H) +。
Embodiment 211C
6-(2-chloro-phenyl-)-2-(4-[4-(trimethylene oxide-3-yl) piperazine-1-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 130B, prepare title compound, with embodiment 211B alternate embodiment 130A.Before HPLC purifying, need not carry out aqueous solution processing. 1H NMR(400 MHz, CD 3OD)δ 3.60-3.26(m, 8H), 4.52-4.45(m, 1H), 4.95-4.84(m, 4H), 7.05(d, J=2.0 Hz, 1H), 7.13-7.08(m, 2H), 7.61-7.53(m, 3H), 7.84-7.66(m, 4H), 9.09(s, 1H)。MS(ESI +)m/z 529.2(M+H) +。
Embodiment 212
6-(the chloro-4-fluorophenyl of 2,6-bis-)-2-[(2,4,4-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-7-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 123B, prepare title compound, with 2,4,4-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-7-amine substitutes 4-(4-methylpiperazine-1-yl) aniline.Carry out aqueous solution processing, then carry out HPLC purifying. 1H NMR(400 MHz, CD 3OD)δ 1.46(s, 6H), 3.12(s, 3H), 3.66-3.31(m, 2H), 4.64-4.38(m, 2H), 7.10(d, J=1.8 Hz, 1H), 7.61-7.53(m, 3H), 7.81-7.69(m, 2H), 7.90(d, J=1.7 Hz, 1H), 9.19(s, 1H)。MS(ESI +)m/z 538.2(M+H) +。
Embodiment 213
6-(2,6-dichlorophenyl)-2-[(4-oxo-Isosorbide-5-Nitrae-dihydro cinnolines-6-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 150, prepare title compound (0.055 g), by amino cinnolines-4 (1H) of 6--one, substitute 1,1,2-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-6-amine.
With Analogix 280 (SF 12-24 post), carry out chromatographic separation, use 0% to 6% ethanol/methylene gradient elution 30 minutes. 1H NMR(300 MHz, DMSO-d 6) δ 7.19(s, 1 H)7.51-7.85(m, 6 H)7.94(s, 1 H)8.19(dd, J=9.32, 2.58 Hz, 1 H)8.85(s, 1 H)9.23(s, 1 H)11.24(s, 1 H)。MS(ESI +)m/z 491.1(M+H) +。
Embodiment 214
2-{[4-(4-ethanoyl piperazine-1-yl) phenyl] amino }-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 109A, prepare title compound (0.045 g), the alternative 7'-amino-1'H-spiral shell of use 1-(4-(4-aminophenyl) piperazine-1-yl) ethyl ketone [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-2'(3'H)-formic acid tertiary butyl ester.With Analogix 280 (SF 12-24 post), carry out chromatographic separation, use 0% to 5% ethanol/methylene gradient elution 30 minutes, title compound is provided. 1H NMR(300 MHz, DMSO-d 6) δ 2.01-2.10(m, 3 H)3.01-3.24(m, 4 H)3.50-3.67(m, 4 H)6.86-7.27(m, 3 H)7.43-7.97(m, 6 H)9.11(s, 1 H)10.74(s, 1 H)。MS(ESI +)m/z 549.2(M+H) +。
Embodiment 215
6-(2,6-dichlorophenyl)-2-(4-[4-(dimethylamino) piperidin-1-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 150, prepare title compound (0.06 g), with the chloro-4-of 3-(4-methylpiperazine-1-yl) aniline, substitute 1,1,2-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-6-amine.With Analogix 280 (SF 12-25 post), carry out chromatographic separation, use 0% to 10% ethanol/methylene gradient elution 30 minutes, 10% methanol-eluted fractions 30 minutes, provides title compound. 1H NMR(300 MHz, DMSO-d 6) δ 1.36-1.63(m, 2 H)1.84(s, 2 H)2.14-2.35(m, 7 H)2.57-2.80(m, 2 H)3.71(d, J=12.21 Hz, 2 H)6.82-7.20(m, 3 H)7.43-8.00(m, 6 H)9.09(s, 1 H)10.56-10.89(m, 1 H)。MS(ESI +)m/z 549.1(M+H) +。
Embodiment 216
4-{[6-(2,6-dichlorophenyl)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } methyl benzoate
As described in embodiment 109A, prepare title compound (0.6 g), the alternative 7'-amino-1'H-spiral shell of use PABA methyl esters [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-2'(3'H)-formic acid tertiary butyl ester.Crude product is ground together with methylene dichloride, title compound is provided. 1H NMR(300 MHz, DMSO-d 6) δ 3.67-3.99(m, 3 H)7.14(d, J=2.03 Hz, 1 H)7.49-7.90(m, 3 H)8.04(s, 5 H)9.24(s, 1 H)11.19(s, 1 H)。MS(ESI +)m/z 481.2(M+H) +。
Embodiment 217
6-(2-chloro-phenyl-)-2-{[3, the chloro-4-of 5-bis-(piperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 217A
4-(2,6-, bis-chloro-4 nitrophenyls) piperazine-1-formic acid tertiary butyl ester
As described in embodiment 183A, prepare title compound, with the chloro-4-fluoronitrobenzene of 3,5-bis-, substitute the fluoro-4-oil of mirbane of 1-, 1-boc-piperazine substitutes two (2-methoxy ethyl) amine.MS(ESI +)m/e 276.0(M + H) +。
Embodiment 217B
4-(4-amino-2,6-dichlorophenyl) piperazine-1-formic acid tertiary butyl ester
In nitrogen gas stream, by embodiment 217A (216 mg, 0.57 mmol) strong stirring in tetrahydrofuran (THF) (10 mL).In this stirred solution, add platinum oxide (IV) (44 mg).At H 2under sacculus condition, this reaction is at room temperature stirred 24 hours.By this reaction of diatomite filtration, remove catalyzer, concentrated, title compound is provided.MS(ESI +)m/e 346.1(M + H) +。
Embodiment 217C
6-(2-chloro-phenyl-)-2-{[3, the chloro-4-of 5-bis-(piperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 203C, prepare title compound, with embodiment 217B alternate embodiment 203B. 1H NMR(500 MHz, DMSO-d 6) δ 10.99(br s, 1H), 9.20(s, 1H), 7.97(s, 2H), 7.73(m, 1H), 7.62(m, 4H), 7.13(s, 1H), 3.36(m, 4H), 3.22(m, 4H)。MS(ESI +)m/e 543.1(M + H) +。
Embodiment 218
6-(2-chloro-phenyl-)-2-{[4-(imidazo [1,2-a] pyridine-2-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 183C, prepare title compound, with 4-imidazo [1,2-a] pyridine-2-base aniline alternate embodiment 183B. 1H NMR(500 MHz, DMSO-d 6) δ 11.04(br s, 1H), 9.20(s, 1H), 8.82(d, 1H), 8.66(s, 1H), 8.04(m, 4H), 7.89(d, 2H), 7.79(m, 1H), 7.73(m, 1H), 7.62(m, 3H), 7.37(t, 1H), 7.12(s, 1H)).MS(ESI +)m/e 505.2(M + H) +。
Embodiment 219
6-(2-chloro-phenyl-)-2-(4-[4-oxo-3-(third-2-yl)-1,3-thiazoles alkane-2-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 183C, prepare title compound, with 2-(4-aminophenyl)-3-sec.-propyl thiazolidin-4-one alternate embodiment 183B. 1H NMR(500 MHz, DMSO-d 6) δ 10.87(br s, 1H), 9.15(s, 1H), 7.89(m, 3H), 7.12(m, 1H), 7.60(m, 3H), 7.49(m, 2H), 7.09(s, 1H), 5.89(s, 1H), 3.94(m, 2H), 3.58(s, 1H), 1.20(d, 3H), 0.90(d, 3H)。MS(ESI +)m/e 532.2(M + H) +。
Embodiment 220
6-(2-chloro-phenyl-)-2-{[4-(2,3-glyoxalidine is [2,1-b] [1,3] thiazole-6-yl also) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 183C, prepare title compound, with 4-(2,3-glyoxalidine is [2,1-b] [1,3] thiazole-6-yl also) aniline alternate embodiment 183B. 1H NMR(500 MHz, DMSO-d 6) δ 10.91(br s, 1H), 9.16(s, 1H), 7.92(m, 4H), 7.73(m, 3H), 7.60(m, 3H), 7.10(s, 1H), 4.40(t, 2H), 4.08(t, 2H)。MS(ESI +)m/e 513.2(M + H) +。
Embodiment 221
6-(2-chloro-phenyl-)-2-{[4-(5-methyl-4-oxo-1,3-thiazoles alkane-2-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 221A
5-methyl-2-(4-nitrophenyl) thiazole-4-alcohol
The mixture of 4-nitrobenzonitrile (5g, 33.8 mmol), thioacetic acid (4.73 g, 44.6 mmol) and pyridine (0.8 mL) is heated to 100 ℃, keeps 2 hours.Ethanol is joined in the cooling mixture of part, and be cooled to room temperature.Collecting precipitation, rinses with ethanol and diethyl ether, and title compound is provided.
Embodiment 221B
2-(4-aminophenyl)-5-methylthiazol alkane-4-ketone
Under 30 psi, in methyl alcohol (100 mL), to embodiment 221A (2.3 g, 1 mmol) and 5% Pd/C (2 g) hydrogenation 4 hours.By this mixture of diatomite filtration.Concentrated filtrate, with purification by flash chromatography (1% CH 3oH/CH 2cl 2), title compound is provided.
Embodiment 221C
6-(2-chloro-phenyl-)-2-{[4-(5-methyl-4-oxo-1,3-thiazoles alkane-2-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 183C, prepare title compound, with embodiment 221B alternate embodiment 183B. 1H NMR(400 Mz, DMSO-d 6) δ 10.82(br s, 1H), 9.13(s, 1H), 8.95(s, 1H)7.86(m, 3H), 7.70(m, 1H), 7.57(m, 3H), 7.45(m, 2H), 7.06(m, 1H), 3.93(m, 1H), 1.45(m, 3H)。MS(ESI +)m/e 504.1(M + H) +。
Embodiment 222
6-(2-chloro-phenyl-)-2-{[4-(imidazo [2,1-b] [1,3] thiazole-6-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 183C, prepare title compound, with 4-(imidazo [2,1-b] thiazole-6-yl) aniline alternate embodiment 183B. 1H NMR(400 MHz, DMSO-d 6) δ 0.86(br s, 1H), 9.15(s, 1H), 8.22(s, 1H), 7.95(m, 6H), 7.73(m, 1H), 7.60(m, 3H), 7.30(d, 1H), 7.09(s, 1H)。MS(ESI +)m/e 511.2(M + H) +。
Embodiment 223
6-(2-chloro-phenyl-)-2-{[4-(3-oxo-2,3-dihydro-1H-indazole-7-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 223A
The bromo-2-fluorophenyl carbamate of 3-
In DMF (50 mL) solution of the bromo-2-fluorobenzoic acid of 3-(10 g, 0.045 mol), add dropwise methyl iodide (5 mL).This reaction is heated to 50 ℃, keeps 24 hours.After this is reacted to cooling and water (500 mL) dilution, add ethyl acetate (200 mL).Separated organic phase, uses MgSO 4dry, filter, concentrated, title compound is provided.
Embodiment 223B
4'-amino-2-fluorine biphenyl-3-methyl-formiate
In glycol dimethyl ether (25 mL) solution of embodiment 223A (3.1 g, 13 mmol), add (4-aminophenyl) boric acid (2.77 g, 16 mmol) and Na 2cO 3(3.38 g, 31.2 mmol) (in water (6 mL)), then adds 1'-bis-(diphenylphosphino) ferrocene-palladium chloride (II) thing: methylene dichloride mixture (652 mg, 0.8 mmol).This mixture is heated to 85 ℃, keeps 10 hours.Be cooled to after room temperature, this reaction mixture is distributed between water and ethyl acetate.Wash organic phase with water, then use salt water washing, then use dried over mgso.After filtering and concentrating, with purification by flash chromatography crude product (1%-100% ethyl acetate/hexane), provide title compound.
Embodiment 223C
7-(4-aminophenyl)-1H-indazole-3 (2H)-one
In microwave phial, embodiment 223B (255 mg, 1.04 mmol), tosic acid monohydrate (98 mg, 0.51 mmol) and hydrazine (1.1 mL) are irradiated 20 minutes at 200 ℃.With RP-HPLC, purify crude mixture, title compound is provided.
Embodiment 223D
6-(2-chloro-phenyl-)-2-{[4-(3-oxo-2,3-dihydro-1H-indazole-7-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 183C, prepare title compound, with embodiment 223C alternate embodiment 183B. 1H NMR(400 MHz, DMSO-d 6, 90o C) δ 10.60(br s, 1H), 9.41(s, 1H), 7.98(m, 2H), 7.83(m, 1H), 7.75(m, 2H), 7.67(m, 1H), 7.58(m, 4H), 7.42(m, 1H), 7.08(m, 2H)。MS(ESI +)m/e 521.2(M +H) +。
Embodiment 224
6-(the chloro-6-fluorophenyl of 2-)-2-{[2'-(2,2-, bis-fluoro ethyls)-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl] amino imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 224A
2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-amine
To 7'-amino-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-2'(3'H) CH of-formic acid tertiary butyl ester (0.350 g, 1.276 mmol) 2cl 2in (8 mL) solution, add trifluoroacetic acid (0.983 mL, 12.76 mmol).Stir this reaction and spend the night, concentrate, the trifluoroacetate of title compound is provided.
Embodiment 224B
2'-(2,2-, bis-fluoro ethyls)-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-amine
In acetonitrile (10 mL) solution of embodiment 224A (245 mg, 0.850 mmol), add salt of wormwood (587 mg, 4.25 mmol).After 15 minutes, add the fluoro-2-iodoethane of 1,1-bis-(0.150 mL, 1.700 mmol), and by this reaction mixture in the phial of adding a cover, 80 ℃ heating 5 hours.After cooling, leach this suspension.Concentrated filtrate, and on 40 g posts purifying, use ISCO Companion flash chromatographic system, with methanol/ethyl acetate (1:99) wash-out, provide title compound.
Embodiment 224C
6-(the chloro-6-fluorophenyl of 2-)-2-{[2'-(2,2-, bis-fluoro ethyls)-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl] amino imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 123B, prepare title compound, with embodiment 95C and embodiment 224B difference alternate embodiment 123A and 4-(4-methylpiperazine-1-yl) aniline.Carry out aqueous solution processing, then carry out HPLC purifying. 1H NMR(400 MHz, CD 3OD)δ 1.31-1.21(m, 4H), 3.58(s, 2H), 3.99-3.80(m, 2H), 4.74(s, 2H), 6.66-6.35(m, 1H), 6.97-6.95(m, 1H), 7.08(d, J=1.8 Hz, 1H), 7.43-7.29(m, 1H), 7.54(dt, J=8.2, 1.2 Hz, 1H), 7.93-7.57(m, 4H), 9.19-9.12(m, 1H)。MS(ESI +)m/z 552.2(M+H) +。
Embodiment 225
6-(the chloro-6-fluorophenyl of 2-)-2-{[2'-(2-fluoro ethyl)-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl] amino imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 225A
2'-(2-fluoro ethyl)-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-amine
As described in embodiment 224B, prepare title compound, with the fluoro-2-iodoethane of 1-, substitute the fluoro-2-iodoethane of 1,1-bis-.
Embodiment 225B
6-(the chloro-6-fluorophenyl of 2-)-2-{[2'-(2-fluoro ethyl)-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl] amino imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 123B, prepare title compound, with embodiment 95C and embodiment 225A difference alternate embodiment 123A and 4-(4-methylpiperazine-1-yl) aniline.Carry out aqueous solution processing, then carry out HPLC purifying. 1H NMR(400 MHz, CD 3OD)δ 1.45-1.15(m, 4H), 3.57(bs, 2H), 3.82-3.69(m, 2H), 4.74(bs, 2H), 5.07-4.87(m, 2H), 6.97(d, J=8.2 Hz, 1H), 7.08(d, J=1.9 Hz, 1H), 7.44-7.34(m, 1H), 7.54(dt, J=8.2, 1.2 Hz, 1H), 7.83-7.57(m, 3H), 7.88(d, J=1.4 Hz, 1H), 9.18(s, 1H)。MS(ESI +)m/z 534.1(M+H) +。
Embodiment 226
6-(the chloro-6-fluorophenyl of 2-)-2-{[2-(diethylamino)-2,3-dihydro-1H-indenes-5-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 226A
N, N-diethyl-2,3-dihydro-1H-indenes-2-amine
To 1H-indenes-2 (3H)-one (6.00 g, 45.4 mmol) in methyl alcohol (100 mL) solution, add diethylamine (6.64 g, 91 mmol), sodium cyanoborohydride (5.71 g, 91 mmol) and acetic acid (5.45 g, 91 mmol).This reaction mixture is stirred and spent the night, and concentrated.With methylene dichloride, dilute resistates, use saturated NaHCO 3the aqueous solution (2 x 50 mL) washing, uses Na 2sO 4dry, filter, concentrated.The resistates obtaining is dissolved in the 1M HCl aqueous solution (100 ml), and extracts with methylene dichloride (2 x 50 mL).With the 6N NaOH aqueous solution, process water layer, until pH=14, and extract with methylene dichloride (4 x 100 mL).Use Na 2sO 4the dry organic layer merging, filters, concentrated, and title compound is provided.
Embodiment 226B
N, N-diethyl-5-nitro-2,3-dihydro-1H-indenes-2-amine
At 0 ℃, in trifluoroacetic acid (80 mL, the 1038 mmol) solution of embodiment 226A (2.0 g, 10.57 mmol), dropwise add nitric acid (0.726 mL, 10.57 mmol).This mixture is stirred 5 hours at 0-15 ℃.This solution is poured in ice/water (20 mL), and used NH 3/ water is adjusted to 10 by pH value.With methylene dichloride (4 x 50 mL), extract this mixture.Use Na 2sO 4the dry organic layer merging, filters, concentrated, and title compound is provided.
Embodiment 226C
N 2, N 2-diethyl-2,3-dihydro-1H-indenes-2,5-diamines
In methyl alcohol (50 mL) solution of embodiment 226B (2.0 g, 8.54 mmol), add Pd/C (10%, 2 g).In this mixture, blast hydrogen, and stir and spend the night.By Celite pad, filter this reaction mixture, and concentrated.With HPLC, purify crude product (C18 post, mobile phase A: 10mM NH 4hCO 3/ water, mobile phase B: acetonitrile, 50-75% B), title compound is provided.MS m/z: 205(M+H) +。 1H NMR(400 MHz, CDCl 3): δ 6.95(d, J=8.0 Hz, 1 H), 6.54(s, 1 H), 6.46(dd, J=7.6, 2.0 Hz, 1 H), 3.61-3.54(m, 1 H), 2.97-2.91(m, 2 H), 2.83-2.73(m, 2 H), 2.64(q, J=7.2 Hz, 4 H), 1.05(t, J=6.8 Hz, 6 H)。
Embodiment 226D
6-(the chloro-6-fluorophenyl of 2-)-2-{[2-(diethylamino)-2,3-dihydro-1H-indenes-5-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 123B, prepare title compound, with embodiment 95C and embodiment 226C difference alternate embodiment 123A and 4-(4-methylpiperazine-1-yl) aniline.Carry out aqueous solution processing, then carry out HPLC purifying. 1H NMR(400 MHz, CD 3OD)δ 1.46-1.32(m, 6H), 3.54-3.17(m, 8H), 4.39-4.31(m, 1H), 7.07(d, J=1.9 Hz, 1H), 7.47-7.22(m, 2H), 7.68-7.45(m, 3H), 7.88-7.77(m, 2H), 9.12(bs, 1H)。MS(ESI +)m/z 518.2(M+H) +。
Embodiment 227
6-(the chloro-6-fluorophenyl of 2-)-2-{[2-(cyclopropylamino)-2,3-dihydro-1H-indenes-5-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 227A
N 2-cyclopropyl-2,3-dihydro-1H-indenes-2,5-diamines
As described in embodiment 226A, embodiment 226B and embodiment 226C, prepare title compound, with cyclopropylamine, substitute diethylamine.MS m/z: 221(M+H) +。
1H NMR(400 MHz, DMSO-d 6): δ 6.80(d, J=8.0 Hz, 1 H), 6.40(s, 1 H), 6.32(dd, J=8.0, 6.0 Hz, 1 H), 5.28-5.25(m, 0.5 H), 5.14-5.11(m, 0.5 H), 4.77(s, 2 H), 2.98-2.91(m, 1 H), 2.86-2.77(m, 4 H), 2.71-2.56(m, 3 H), 2.20-2.05(m, 1 H), 1.94-1.79(m, 1 H)。
Embodiment 227B
6-(the chloro-6-fluorophenyl of 2-)-2-{[2-(cyclopropylamino)-2,3-dihydro-1H-indenes-5-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 123B, prepare title compound, with embodiment 95C and embodiment 227A difference alternate embodiment 123A and 4-(4-methylpiperazine-1-yl) aniline.Carry out aqueous solution processing, then carry out HPLC purifying. 1H NMR(400 MHz, CD 3OD)δ 1.02-0.82(m, 4H), 2.92-2.80(m, 1H), 3.25-3.11(m, 2H), 3.58-3.42(m, 2H), 4.31-4.21(m, 1H), 7.08(d, J=1.9 Hz, 1H), 7.43-7.27(m, 2H), 7.70-7.47(m, 3H), 7.86-7.78(m, 2H), 9.15(s, 1H)。MS(ESI +)m/z 502.2(M+H) +。
Embodiment 228
6-(the chloro-6-fluorophenyl of 2-)-2-(2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-base amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 160A and embodiment 160B, prepare title compound, with embodiment 95C alternate embodiment 123A.
Embodiment 229
2-{[4-(Isosorbide-5-Nitrae '-Lian piperidines-1'-yl) phenyl] amino-6-(2-chloro-phenyl-) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 229A
1'-(4-nitrophenyl)-Isosorbide-5-Nitrae '-Lian piperidines
As described in embodiment 183A, prepare title compound, with 4-piperidino-(1-position only) piperidines, substitute two (2-methoxy ethyl) amine.MS(ESI +)m/e 290.1(M +H) +。
Embodiment 229B
4-(Isosorbide-5-Nitrae '-Lian piperidines-1'-yl) aniline
As described in embodiment 183B, prepare title compound, with embodiment 229A alternate embodiment 183A.MS(ESI +)m/e 260.2(M + H) +。
Embodiment 229C
2-{[4-(Isosorbide-5-Nitrae '-Lian piperidines-1'-yl) phenyl] amino-6-(2-chloro-phenyl-) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 183C, prepare title compound, with embodiment 229B alternate embodiment 183B. 1H NMR(400 MHz, DMSO-d 6) δ 10.65(br s, 1H), 9.08(s, 1H), 7.72(m, 3H), 7.58(m, 4H), 7.07(m, 3H), 3.87(M, 2H), 3.47(m, 4H), 2.95(m, 2H), 2.73(m, 2H), 2.10(m, 2H), 1.78(m, 6H), 1.42(m, 1H)。MS(ESI +)m/e 555.2(M +H) +。
Embodiment 230
6-(2-chloro-phenyl-)-2-(4-[(3R) and-3-(dimethylamino) pyrrolidin-1-yl] phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 230A
(R)-N, N-dimethyl-1-(4-nitrophenyl) tetramethyleneimine-3-amine
As described in embodiment 183A, prepare title compound, with (R)-N, N-dimethyl pyrrolidine-3-amine substitutes two (2-methoxy ethyl) amine.MS(ESI +)m/e 236.2(M + H) +。
Embodiment 230B
(R)-1-(4-aminophenyl)-N, N-dimethyl pyrrolidine-3-amine
As described in embodiment 183B, prepare title compound, with embodiment 230A alternate embodiment 183A.
Embodiment 230C
6-(2-chloro-phenyl-)-2-(4-[(3R) and-3-(dimethylamino) pyrrolidin-1-yl] phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 183C, prepare title compound, with embodiment 230B alternate embodiment 183B. 1H NMR(400 MHz, DMSO-d 6) δ 10.58(br s, 1H), 9.05(s, 1H), 7.73(m, 3H), 7.58(m, 4H), 7.06(s, 1H), 6.72(m, 2H), 4.02(m, 1H), 3.62(m, 1H), 3.45(m, 2H), 3.27(m, 1H), 2.87(s, 6H), 2.45(m, 1H), 2.21(m, 1H)。MS(ESI +)m/e 501.2(M + H) +。
Embodiment 231
6-(2-chloro-phenyl-)-2-(4-[3-(trifluoromethyl) piperidin-1-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 231A
1-(4-nitrophenyl)-3-(trifluoromethyl) piperidines
As described in embodiment 183A, prepare title compound, with 3-(trifluoromethyl) piperidines, substitute two (2-methoxy ethyl) amine.MS(ESI +)m/e 275.1(M + H) +。
Embodiment 231B
4-(3-(trifluoromethyl) piperidin-1-yl) aniline
As described in embodiment 183B, prepare title compound, with embodiment 231A alternate embodiment 183A.
Embodiment 231C
6-(2-chloro-phenyl-)-2-(4-[3-(trifluoromethyl) piperidin-1-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 183C, prepare title compound, with embodiment 231B alternate embodiment 183B. 1H NMR(400 MHz, DMSO-d 6) δ 10.65(br s, 1H), 9.08(s, 1H), 7.65(m, 7H), 7.07(m, 3H), 3.74(m, 2H), 2.71(m, 3H), 1.96(m, 1H), 1.82(m, 1H), 1.65(m, 1H), 1.46(m, 1H)。MS(ESI +)m/e 540.3(M + H) +。
Embodiment 232
3-[4-(4-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } phenyl) piperazine-1-yl] propionitrile
Embodiment 232A
3-(4-(4-nitrophenyl) piperazine-1-yl) propionitrile
As described in embodiment 183A, prepare title compound, with 3-(piperazine-1-yl) propionitrile, substitute two (2-methoxy ethyl) amine.MS(ESI +)m/e 261.2(M + H) +。
Embodiment 232B
3-(4-(4-aminophenyl) piperazine-1-yl) propionitrile
As described in embodiment 183B, prepare title compound, with embodiment 232B alternate embodiment 183B.
Embodiment 232C
3-[4-(4-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } phenyl) piperazine-1-yl] propionitrile
As described in embodiment 183C, prepare title compound, with embodiment 232B alternate embodiment 183B. 1H NMR(400 MHz, DMSO-d 6) δ 10.67(br s, 1H), 9.08(s, 1H)7.64(m, 7H), 7.07(m, 3H), 3.55(m, 4H), 3.07(m, 4H)。MS(ESI +)m/e 526.3(M + H) +。
Embodiment 233
3-[(4-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } phenyl) (cyclopropyl) amino] propionitrile
Embodiment 233A
3-(cyclopropyl (4-nitrophenyl) amino) propionitrile
As described in embodiment 183A, prepare title compound, with 3-(cyclopropylamino) propionitrile, substitute two (2-methoxy ethyl) amine.
Embodiment 233B
3-((4-aminophenyl) (cyclopropyl) amino) propionitrile
As described in embodiment 183B, prepare title compound, with embodiment 233A alternate embodiment 183A.
Embodiment 233C
3-[(4-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } phenyl) (cyclopropyl) amino] propionitrile
As described in embodiment 183C, prepare title compound, with embodiment 232B alternate embodiment 183B. 1H NMR(400 MHz, DMSO-d 6) δ 10.62(br s, 1H), 9.06(s, 1H), 7.64(m, 7H), 7.09(m, 3H), 3.72(m, 2H), 2.72(m, 2H), 2.57(m, 1H), 0.88(m, 2H), 0.58(m, 2H)。MS(ESI +)m/e 497.2(M + H) +。
Embodiment 234
6-(2-chloro-phenyl-)-2-[(4-{[2-(dimethylamino) ethyl] amino } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 234A
N 1, N 1-dimethyl-N 2-(4-nitrophenyl) ethane-1,2-diamines
As described in embodiment 183A, prepare title compound, use N 1, N 1-dimethyl ethane-1,2-diamines substitutes two (2-methoxy ethyl) amine.MS(ESI +)m/e 210.1(M + H) +。
Embodiment 234B
N 1-(2-(dimethylamino) ethyl) benzene-Isosorbide-5-Nitrae-diamines
As described in embodiment 183B, prepare title compound, with embodiment 234A alternate embodiment 183A.
Embodiment 234C
6-(2-chloro-phenyl-)-2-[(4-{[2-(dimethylamino) ethyl] amino } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 183C, prepare title compound, with embodiment 234B alternate embodiment 183B. 1H NMR(400 MHz, DMSO-d 6) δ 10.55(br s, 1H)9.04(s, 1H), 7.73(m, 2H), 7.59(m, 5H), 7.06(s, 1H), 6.72(m, 2H), 3.42(m, 2H), 3.27(m, 2H), 2.85(s, 6H)。MS(ESI +)m/e 475.2(M + H) +。
Embodiment 235
1-(4-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } phenyl) piperidines-4-methane amide
Embodiment 235A
1-(4-nitrophenyl) piperidines-4-methane amide
As described in embodiment 183A, prepare title compound, with piperidines-4-methane amide, substitute two (2-methoxy ethyl) amine.
Embodiment 235B
1-(4-aminophenyl) piperidines-4-methane amide
As described in embodiment 183B, prepare title compound, with embodiment 235A alternate embodiment 182A.
Embodiment 235C
1-(4-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } phenyl) piperidines-4-methane amide
As described in embodiment 183C, prepare title compound, with embodiment 235B alternate embodiment 183B. 1H NMR(400 MHz, DMSO-d 6) δ 10.62(br s, 1H), 9.13(s, 1H), 7.80(m, 4H), 7.60(m, 3H), 7.42(m, 3H), 7.09(s, 1H). .6.91(s, 1H), 3.69(m, 2H), 3.17(m, 2H), 2.42(m, 1H), 1.89(m, 4H)。MS(ESI +)m/e 515.2(M + H) +。
Embodiment 236
6-(2-chloro-phenyl-)-2-(4-[4-(morpholine-4-yl) piperidin-1-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 236A
4-(1-(4-nitrophenyl) piperidin-4-yl) morpholine
As described in embodiment 183A, prepare title compound, with 4-(piperidin-4-yl) morpholine, substitute two (2-methoxy ethyl) amine.MS(ESI +)m/e 292.1(M + H) +。
Embodiment 236B
4-(4-morpholino piperidin-1-yl) aniline
As described in embodiment 183B, prepare title compound, with embodiment 236A alternate embodiment 183A.
Embodiment 236C
6-(2-chloro-phenyl-)-2-(4-[4-(morpholine-4-yl) piperidin-1-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 183C, prepare title compound, with embodiment 236B alternate embodiment 183B.Use 1:1 DMSO:CH 3oH, by crude product recrystallization, provides the free alkali of title compound. 1H NMR(400 MHz, DMSO-d 6, 120 o C) δ 10.02(br s, 1H), 9.02(s, 1H), 7.59(m, 7H), 7.01(s, 1H), 6.95(d, 2H), 3.68(m, 2H)3.59(m, 4H), 2.75(m, 1H), 2.51(m, 5H),2.33(m, 1H), 1.86(m, 2H),1.57(m, 2H)。
Embodiment 237
6-(2,6-dichlorophenyl)-2-[(4-{[4-(dimethylamino) piperidin-1-yl] carbonyl } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 237A
4-{[6-(2,6-dichlorophenyl)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } phenylformic acid
In the 10 mL methyl alcohol of embodiment 216 (0.6g, 1.24mmol) and the suspension of 3 mL water, add KOH (0.28 g, 4.99 mmol).This is reacted in 50 degree heated overnight, and 60 degree heating 1.5 hours.This reaction mixture is cooling, and concentrated.Crude product is suspended in ethyl acetate, with 1M HCl acidified aqueous solution, with methylene dichloride (2x), extracts water layer.The organism that water and salt water washing merge, uses MgSO 4dry, filter, concentrated.Material in water layer is filtered, and by solid drying, provide title compound.MS(ESI +)m/z 467.2 (M+H) +。
Embodiment 237B
6-(2,6-dichlorophenyl)-2-[(4-{[4-(dimethylamino) piperidin-1-yl] carbonyl } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
To embodiment 237A (100 mg, 0.214 mmol) 5 mL N, in dinethylformamide solution, add 1-ethyl-3-[3-(dimethylamino) propyl group]-carbodiimide hydrochloride (61.5 mg, 0.321 mmol), I-hydroxybenzotriazole hydrate (49.2 mg, 0.321 mmol), diisopropylethylamine (0.075 mL, 0.428 mmol), then add N, N-lupetidine-4-amine (0.036 mL, 0.257 mmol).This reaction mixture is at room temperature kept spending the night, then by ethyl acetate, dilute.Use saturated NaHCO 3the aqueous solution, water and salt water washing organism, then use MgSO 4dry, filter, concentrated.From crude product reaction mixture, grind out compound, title compound is provided. 1H NMR(300 MHz, DMSO-d 6) δ 1.21-1.55(m, 2 H)1.63-1.98(m, 2 H)2.13-2.43(m, 6 H)2.73-3.12(m, 2 H)7.14(d, J=1.59 Hz, 1 H)7.48(d, J=8.73 Hz, 2 H)7.58-7.81(m, 4 H)7.86-8.02(m, 3 H)9.06-9.33(m, 1 H)11.04(s, 1 H)。MS(ESI +)m/z 477.1 (M+H) +。
Embodiment 238
4-{[6-(2,6-dichlorophenyl)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino }-N-[4-(dimethylamino) cyclohexyl] benzamide
As described in embodiment 237B, prepare title compound (0.03 g), use N 1, N 1-dimethyl cyclohexane-Isosorbide-5-Nitrae-diamines substitutes N, N-lupetidine-4-amine.Use ethyl acetate, from crude product reaction mixture, grind out compound. 1H NMR(300 MHz, DMSO-d 6) δ 1.59(t, 4 H)2.03(t, 4 H)2.57-2.78(m, 6 H)3.08(t, 1 H)3.78(t, 1 H)7.14(t, J=1.86 Hz, 1 H)7.52-7.72(m, 1 H)7.70-7.83(m, 2 H)7.93(d, J=1.70 Hz, 5 H)8.22(d, J=7.80 Hz, 1 H)9.22(s, 1 H)11.05(s, 1 H)。MS(ESI +)m/z 591.1(M+H) +。
Embodiment 239
4-{[6-(2,6-dichlorophenyl)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino }-N-(1-methyl piperidine-4-yl) benzamide
As described in embodiment 237B, prepare title compound (0.015 g), with 1-methyl piperidine-4-amine, substitute N, N-lupetidine-4-amine.Use ethyl acetate, from crude product reaction mixture, grind out compound. 1H NMR(300 MHz, DMSO-d 6) δ 1.82(d, J=54.75 Hz, 4 H)3.19-3.28(m, 3 H)3.77-4.05(m, 2 H)7.14(d, J=1.98 Hz, 1 H)7.53-7.72(m, 1 H)7.71-7.85(m, 2 H)7.84-8.07(m, 6 H)8.16-8.42(m, 1 H)9.14-9.28(m, 1 H)11.06(s, 1 H)。MS(ESI +)m/z 563.1(M+H) +。
Embodiment 240
6-(2,6-dichlorophenyl)-2-(4-[4-(pyrrolidin-1-yl) piperidin-1-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 150, prepare title compound (0.07 g), with 4-(4-(pyrrolidin-1-yl) piperidin-1-yl) aniline, substitute 1,1,2-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-6-amine.Use ethyl acetate, from crude product reaction mixture, grind out compound. 1H NMR(300 MHz, DMSO-d 6) δ 1.39-1.62(m, 2 H)1.60-1.78(m, 4 H)1.81-1.99(m, 3 H)2.04-2.24(m, 1 H)2.59-2.84(m, 2 H)3.47-3.74(m, 2 H)6.77-7.20(m, 3 H)7.35-7.93(m, 6 H)9.09(s, 1 H)10.70(s, 1 H)。MS(ESI +)m/z 575.2(M+H) +。
Embodiment 241
2-[(2'-ethanoyl-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl) amino]-6-(the chloro-6-fluorophenyl of 2-) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
By embodiment 228 (0.075 g, 0.134 mmol), acetic acid (0.011 mL, 0.201 mmol), benzotriazole-1-base oxygen base tripyrrole alkane Ji Phosphonium hexafluorophosphate (0.104 g, 0.201 mmol) and triethylamine (0.093 mL, 0.669 mmol) DMF (2.5 mL) solution stirring is spent the night.Water is joined in this reaction mixture at leisure.By the solid filtering obtaining, wash with water, further with reversed-phase HPLC, purify (at Zorbax RX-C18 post (250 x 21.2 mm, 7 μ m particle diameters) on, carry out), use 10% to 95% acetonitrile: 0.1% trifluoroacetic acid aqueous solution gradient elution 35 minutes, flow velocity 15 mL/ minute, provide the trifluoroacetate of title compound. 1H NMR(400 MHz, CD 3OD)δ 1.10-0.98(m, 4H), 2.17(s, 1.7H), 2.23(s, 1.3H), 3.62(d, J=4.4 Hz, 2H), 4.86(s, 2H), 6.94-6.85(m, 1H), 7.07(d, J=2.1 Hz, 1H), 7.42-7.34(m, 1H), 7.70-7.46(m, 4H), 7.84(bs, 1H), 9.14(bs, 1H)。MS(ESI +)m/z 530.2(M+H) +。
Embodiment 242
6-(the chloro-6-fluorophenyl of 2-)-2-{[2'-(cyclopropyl carbonyl)-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl] amino imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 241, prepare title compound, with cyclopropane-carboxylic acid, substitute acetic acid. 1H NMR(400 MHz, CD 3OD)δ 1.08-0.80(m, 8H), 2.14-1.98(m, 1H), 3.64(s, 0.8H), 3.84(s, 1.2H),), 4.88(s, 1.2 H), 5.09(s, 0.8H), 6.93-6.86(m, 1H), 7.07(d, J=1.9 Hz, 1H), 7.42-7.34(m, 1H), 7.70-7.46(m, 4H), 7.89-7.77(m, 1H), 9.14(bs, 1H)。MS(ESI +)m/z 556.2(M+H) +。
Embodiment 243
6-(the chloro-6-fluorophenyl of 2-)-2-{[2'-(methylsulfonyl)-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl] amino imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 172, prepare title compound, with embodiment 228 alternate embodiment 160B. 1H NMR(400 MHz, CD 3OD)δ 1.17-0.99(m, 4H), 2.90(s, 3H), 3.44(s, 2H), 4.64(s, 2H), 6.94-6.81(m, 1H), 7.08(d, J=1.9 Hz, 1H), 7.42-7.34(m, 1H), 7.70-7.47(m, 4H), 7.85(s, 1H), 9.16(bs, 1H)。MS(ESI +)m/z 566.2(M+H) +。
Embodiment 244
6-(the chloro-6-fluorophenyl of 2-)-2-({ 4-[(8aR)-hexahydropyrrolo is [1,2-a] pyrazine-2 (1H)-yl also] phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 123B, prepare title compound, with embodiment 95C and (R)-4-(hexahydropyrrolo is [1,2-a] pyrazine-2 (1H)-yl also) aniline difference alternate embodiment 123A and 4-(4-methylpiperazine-1-yl) aniline.Carry out aqueous solution processing, then carry out HPLC purifying. 1H NMR(400 MHz, CD 3OD)δ 2.42-1.72(m, 4H), 3.20-2.86(m, 2H), 4.19-3.22(m, 7H), 7.11-7.04(m, 3H), 7.43-7.34(m, 1H), 7.56-7.50(m, 1H), 7.90-7.56(m, 4H), 9.09(bs, 1H)。MS(ESI +)m/z 531.2(M+H) +。
Embodiment 245
2-(4-[(3R) and-1-azabicyclo [2.2.2] oct-3-yl amino] phenyl } amino)-6-(2-chloro-phenyl-) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 245A
(R)-N-(4-nitrophenyl) rubane-3-amine
As described in embodiment 183A, prepare title compound, with (R)-rubane-3-amine, substitute two (methoxy ethyl) amine.MS(ESI +)m/e 248.2(M + H) +。
Embodiment 245B
(R)-N 1-(rubane-3-yl) benzene-Isosorbide-5-Nitrae-diamines
As described in embodiment 183B, prepare title compound, with embodiment 245A alternate embodiment 183A.
Embodiment 245C
2-(4-[(3R) and-1-azabicyclo [2.2.2] oct-3-yl amino] phenyl } amino)-6-(2-chloro-phenyl-) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 183C, prepare title compound, with embodiment 245B alternate embodiment 183B. 1H NMR(400 MHz, DMSO-d 6) δ 10.54(br s, 1H), 9.04(s, 1H), 7.73(m, 2H), 7.59(m, 5H), 7.06(s, 1H), 6.70(m, 2H), 3.85(m, 1H), 3.74(m, 1H), 3.25(m, 4H), 2.94(m, 1H), 2.22(m, 1H), 2.10(m, 1H), 1.94(m, 2H), 1.71(m, 1H)。MS(ESI +)m/e 513.3(M + H) +。
Embodiment 246
6-(2-chloro-phenyl-)-2-[(4-{[2-(pyrrolidin-1-yl) ethyl] amino } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 246A
4-nitro-N-(2-(pyrrolidin-1-yl) ethyl) aniline
As described in embodiment 183A, prepare title compound, with 2-(pyrrolidin-1-yl) ethamine, substitute two (2-methoxy ethyl) amine.MS(ESI +)m/e 236.2(M + H) +。
Embodiment 246B
N 1-(2-(pyrrolidin-1-yl) ethyl) benzene-Isosorbide-5-Nitrae-diamines
As described in embodiment 183B, prepare title compound, with embodiment 246A alternate embodiment 183B.
Embodiment 246C
6-(2-chloro-phenyl-)-2-[(4-{[2-(pyrrolidin-1-yl) ethyl] amino } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 183C, prepare title compound, with embodiment 246B alternate embodiment 183B. 1H NMR(400 MHz, DMSO-d 6, 90o C) δ 10.14(br s, 1H), 9.01(s, 1H), 7.67(m, 2H), 7.54(m, 5H), 7.02(m, 1H), 6.71(d, 2H), 3.45(m, 4H), 3.35(m, 4H), 1.98(m, 4H)。MS(ESI +)m/e 501.2(M + H) +。
Embodiment 247
6-(2-chloro-phenyl-)-2-(4-[4-(pyridine-2-yl) piperazine-1-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 247A
1-(4-nitrophenyl)-4-(pyridine-2-yl) piperazine
As described in embodiment 183A, prepare title compound, with 1-(pyridine-2-yl) piperazine, substitute two (2-methoxy ethyl) amine.MS(ESI +)m/e 285.1(M + H) +。
Embodiment 247B
4-(4-(pyridine-2-yl) piperazine-1-yl) aniline
As described in embodiment 183B, prepare title compound, with embodiment 247A alternate embodiment 183A.
Embodiment 247C
6-(2-chloro-phenyl-)-2-(4-[4-(pyridine-2-yl) piperazine-1-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 183C, prepare title compound, with embodiment 247B alternate embodiment 183B.Use 1:1 DMSO:CH 3oH, by crude product recrystallization, provides the free alkali of title compound. 1H NMR(400 MHz, DMSO-d 6, 90o C) δ 10.24(br s, 1H), 9.04(s, 1H), 8.13(m, 1H), 7.68(m, 4H), 7.54(m, 4H), 7.03(m, 3H), 6.84(d, 1H), 6.64(m, 1H), 3.67(m, 4H), 3.27(m, 4H)。MS(ESI +)m/e 550.3(M + H) +。
Embodiment 248
6-(2-chloro-phenyl-)-2-[(4-{[2-(morpholine-4-yl) ethyl] amino } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 248A
N-(2-morpholino ethyl)-4-N-methyl-p-nitroaniline
As described in embodiment 183A, prepare title compound, with 2-morpholino ethamine, substitute two (2-methoxy ethyl) amine.MS(ESI +)m/e 252.2(M + H) +。
Embodiment 248B
N 1-(2-morpholino ethyl) benzene-Isosorbide-5-Nitrae-diamines
As described in embodiment 183B, prepare title compound, with embodiment 248A alternate embodiment 183A.
Embodiment 248C
6-(2-chloro-phenyl-)-2-[(4-{[2-(morpholine-4-yl) ethyl] amino } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 183C, prepare title compound, with embodiment 248B alternate embodiment 183B. 1H NMR(400 MHz, DMSO-d 6) δ 10.55(br s, 1H), 9.04(s, 1H), 7.72(m, 2H), 7.61(m, 5H), 7.06(s, 1H), 6.73(m, 2H), 3.86(m, 4H), 3.53(m, 4H), 3.31(m, 4H)。MS(ESI +)m/e 517.2(M + H) +。
Embodiment 249
6-(2-chloro-phenyl-)-2-(4-[(2S) and-2-(pyrrolidin-1-yl methyl) pyrrolidin-1-yl] phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 249A
(S)-1-(4-nitrophenyl)-2-(pyrrolidin-1-yl methyl) tetramethyleneimine
As described in embodiment 183A, prepare title compound, with (S)-1,2'-dipyrromethene alkane substitutes two (2-methoxy ethyl) amine.MS(ESI +)m/e 276.2(M + H) +。
Embodiment 249B
(S)-4-(2-(pyrrolidin-1-yl methyl) pyrrolidin-1-yl) aniline
As described in embodiment 183B, prepare title compound, with embodiment 249A alternate embodiment 183A.
Embodiment 249C
6-(2-chloro-phenyl-)-2-(4-[(2S) and-2-(pyrrolidin-1-yl methyl) pyrrolidin-1-yl] phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 183C, prepare title compound, with embodiment 249B alternate embodiment 183B. 1H NMR(400 MHz, DMSO-d 6, 90o C) δ 10.20(br s, 1H), 9.02(s, 1H), 7.59(m, 7H), 7.03(s, 1H), 6.74(d, 2H), 4.12(m, 1H), 3.45(m, 5H), 3.25(m, 3H), 2.05(m, 8H)。MS(ESI +)m/e 541.1(M + H) +。
Embodiment 250
6-(2-chloro-phenyl-)-2-[(4-{4-[3-(dimethylamino) propyl group] piperazine-1-yl } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 250A
N, N-dimethyl-3-(4-(4-nitrophenyl) piperazine-1-yl) third-1-amine
As described in embodiment 183A, prepare title compound, with N, N-dimethyl-3-(piperazine-1-yl) third-1-amine substitutes two (2-methoxy ethyl) amine.MS(ESI +)m/e 293.2(M + H) +。
Embodiment 250B
4-(4-(3-(dimethylamino) propyl group) piperazine-1-yl) aniline
As described in embodiment 183B, prepare title compound, with embodiment 250A alternate embodiment 183A.
Embodiment 250C
6-(2-chloro-phenyl-)-2-[(4-{4-[3-(dimethylamino) propyl group] piperazine-1-yl } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 183C, prepare title compound, with embodiment 250B alternate embodiment 183B. 1H NMR(400 MHz, DMSO-d 6) δ 10.70(br s, 1H), 9.09(s, 1H), 7.64(m, 7H), 7.09(m, 3H), 3.46(m, 4H), 3.16(m, 8H), 2.82(s, 6H), 2.11(m, 2H)。MS(ESI +)m/e 558.2(M + H) +。
Embodiment 251
6-(2-chloro-phenyl-)-2-(4-[(2R) and-2-(methoxymethyl) pyrrolidin-1-yl] phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 251A
(R)-2-(methoxymethyl)-1-(4-nitrophenyl) tetramethyleneimine
As described in embodiment 183A, prepare title compound, with (R)-2-(methoxymethyl) tetramethyleneimine, substitute two (2-methoxy ethyl) amine.MS(ESI +)m/e 237.1(M + H) +。
Embodiment 251B
(R)-4-(2-(methoxymethyl) pyrrolidin-1-yl) aniline
As described in embodiment 183B, prepare title compound, with embodiment 251A alternate embodiment 183A.
Embodiment 251C
6-(2-chloro-phenyl-)-2-(4-[(2R) and-2-(methoxymethyl) pyrrolidin-1-yl] phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 183C, prepare title compound, with embodiment 251B alternate embodiment 183B. 1H NMR(400 MHz, DMSO-d 6 δ 10.55(br s, 1H), 9.03(s, 1H), 7.63(m, 7H), 7.05(s, 1H), 6.70(m, 2H), 3.84(m, 1H), 3.41(m, 2H), 3.30(s, 3H), 3.23(m, 1H), 3.07(m, 1H), 1.95(m, 4H)。MS(ESI +)m/e 502.2(M + H) +。
Embodiment 252
1-(4-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } phenyl)-N, N-diethyl piperidines-3-methane amide
Embodiment 252A
N, N-diethyl-1-(4-nitrophenyl) piperidines-3-methane amide
As described in embodiment 183A, prepare title compound, with N, N-diethyl piperidines-3-methane amide substitutes two (2-methoxy ethyl) amine.MS(ESI +)m/e 306.1(M + H) +。
Embodiment 252B
1-(4-aminophenyl)-N, N-diethyl piperidines-3-methane amide
As described in embodiment 183B, prepare title compound, with embodiment 252A alternate embodiment 183A.
Embodiment 252C
1-(4-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } phenyl)-N, N-diethyl piperidines-3-methane amide
As described in embodiment 183C, prepare title compound, with embodiment 252B alternate embodiment 183B.Use 1:1 DMSO:CH 3oH, by crude product recrystallization, provides the free alkali of title compound. 1H NMR(400 MHz, DMSO-d 6, 90o C) δ 10.20(s, 1H), 9.03(s, 1H), 7.71(s, 1H), 7.59(m, 6H), 7.02(s, 1H), 6.96(d, 2H), 3.66(m, 2H), 3.34(m, 4H), 3.01(m, 1H), 2.77(m, 3H), 1.70(m, 4H), 1.10(m, 5H)。MS(ESI +)m/e 571.2(M + H) +。
Embodiment 253
6-(2-chloro-phenyl-)-2-[(4-{[3-(2-oxo-pyrrolidine-1-yl) propyl group] amino } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 253A
1-(3-(4-nitrophenyl is amino) propyl group) pyrrolidin-2-one
As described in embodiment 183A, prepare title compound, with 1-(3-aminopropyl) pyrrolidin-2-one, substitute two (2-methoxy ethyl) amine.MS(ESI +)m/e 264.2(M + H) +。
Embodiment 253B
1-(3-(4-aminophenyl is amino) propyl group) pyrrolidin-2-one
As described in embodiment 183B, prepare title compound, with embodiment 253A alternate embodiment 183B.
Embodiment 253C
6-(2-chloro-phenyl-)-2-[(4-{[3-(2-oxo-pyrrolidine-1-yl) propyl group] amino } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 183C, prepare title compound, with embodiment 253B alternate embodiment 183B. 1H NMR(400 MHz, DMSO-d 6) δ 10.70(br, s, 1H), 9.10(s, 1H), 7.73(m, 4H), 7.59(m, 3H), 7.06(m, 3H), 3.31(m, 4H), 3.14(t, 2H), 2.25(t, 2H), 1.94(m, 2H), 1.79(m, 2H)。MS(ESI +)m/e 529.2(M + H) +。
Embodiment 254
6-(2-chloro-phenyl-)-2-(4-[4-(4-fluorophenyl) piperazine-1-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 254A
1-(4-fluorophenyl)-4-(4-nitrophenyl) piperazine
As described in embodiment 183A, prepare title compound, with 1-(4-fluorophenyl) piperazine, substitute two (2-methoxy ethyl) amine.MS(ESI +)m/e 302.1(M + H) +。
Embodiment 254B
4-(4-(4-fluorophenyl) piperazine-1-yl) aniline
As described in embodiment 183B, prepare title compound, with embodiment 254A alternate embodiment 183A.
Embodiment 254C
As described in embodiment 183C, prepare title compound, with embodiment 254B alternate embodiment 183B. 1H NMR(400 MHz, DMSO-d 6) δ 10.67(br s, 1H), 9.08(s, 1H), 7.67(m, 7H), 7.08(m, 7H), 3.38(m, 8H)。MS(ESI +)m/e 567.3(M + H) +。
Embodiment 255
6-(the chloro-6-fluorophenyl of 2-)-2-(4-[4-(dimethylamino) piperidin-1-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 123B, prepare title compound, with embodiment 95C and 1-(4-aminophenyl)-N, N-lupetidine-4-amine is alternate embodiment 123A and 4-(4-methylpiperazine-1-yl) aniline respectively.Carry out aqueous solution processing, then carry out HPLC purifying. 1H NMR(500 MHz, CD 3OD)δ 2.00-1.86(m, 2H), 2.26-2.19(m, 2H), 2.98-2.88(m, 8H), 3.40(tt, J=12.1, 3.9 Hz, 1H), 3.93-3.85(m, 2H), 7.18-7.05(m, 3H), 7.39(t, J=8.7 Hz, 1H), 7.53(d, J=8.2 Hz, 1H), 7.94-7.57(m, 4H), 9.13(s, 1H)。MS(ESI +)m/z 533.1(M+H) +。
Embodiment 256
6-(the chloro-6-fluorophenyl of 2-)-2-(2-[(3S) and-3-fluoropyrrolidine-1-yl]-2,3-dihydro-1H-indenes-5-yl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 256A
2-((S)-3-fluoropyrrolidine-1-yl)-2,3-dihydro-1H-indenes-5-amine
As described in embodiment 226A, embodiment 226B and embodiment 226C, prepare title compound, with (S)-3-fluoropyrrolidine, substitute diethylamine.MS m/z: 221(M+H) +。
1HNMR(400 MHz, DMSO-d 6): δ 6.80(d, J=8.0 Hz, 1 H), 6.40(s, 1 H), 6.32(dd, J=8.0, 6.0 Hz, 1 H), 5.28-5.25(m, 0.5 H), 5.14-5.11(m, 0.5 H), 4.77(s, 2 H), 2.98-2.91(m, 1 H), 2.86-2.77(m, 4 H), 2.71-2.56(m, 3 H), 2.20-2.05(m, 1 H), 1.94-1.79(m, 1 H)。
Embodiment 256B
6-(the chloro-6-fluorophenyl of 2-)-2-(2-[(3S) and-3-fluoropyrrolidine-1-yl]-2,3-dihydro-1H-indenes-5-yl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 123B, prepare title compound, with embodiment 95C and embodiment 256A difference alternate embodiment 123A and 4-(4-methylpiperazine-1-yl) aniline.Carry out aqueous solution processing, then carry out HPLC purifying. 1H NMR(500 MHz, CD 3OD)δ 2.69-2.12(m, 2H), 3.26-3.17(m, 2H), 3.60-3.40(m, 4H), 4.11-3.64(m, 2H), 4.26(bs, 1H), 5.58-5.41(m, 1H), 7.07(d, J=1.8 Hz, 1H), 7.47-7.24(m, 2H), 7.69-7.45(m, 3H), 7.91-7.76(m, 2H), 9.13(s, 1H)。MS(ESI +)m/z 534.2(M+H) +。
Embodiment 257
6-(the chloro-6-fluorophenyl of 2-)-2-(2-[(2-fluoro ethyl) and amino]-2,3-dihydro-1H-indenes-5-yl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 257A
N 2-(2-fluoro ethyl)-2,3-dihydro-1H-indenes-2,5-diamines
As described in embodiment 226A, embodiment 226B and embodiment 226C, prepare title compound, with 2-fluorine ethamine, substitute diethylamine.MS m/z: 195(M+H) +。
1HNMR(400 MHz, DMSO-d 6): δ 6.79(d, J=8.0 Hz, 1 H), 6.39(s, 1 H), 6.35(dd, J=7.6, 2.0 Hz, 1 H), 4.74(s, 2 H), 4.51(t, J=4.8 Hz, 1 H), 4.39(t, J=4.8 Hz, 1 H), 3.46-3.41(m, 1 H), 2.93-2.84(m, 3 H), 2.78(t, J=4.2 Hz, 1 H), 2.49-2.43(m, 2 H)。
Embodiment 257B
6-(the chloro-6-fluorophenyl of 2-)-2-(2-[(2-fluoro ethyl) and amino]-2,3-dihydro-1H-indenes-5-yl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 123B, prepare title compound, with embodiment 95C and embodiment 257A difference alternate embodiment 123A and 4-(4-methylpiperazine-1-yl) aniline.Carry out aqueous solution processing, then carry out HPLC purifying. 1H NMR(500 MHz, CD 3OD)δ 3.27-3.09(m, 2H), 3.57-3.41(m, 4H), 4.26-4.17(m, 1H), 4.73(t, J=4.5 Hz, 1H), 4.84-4.82(m, 1H), 7.08(d, J=1.8 Hz, 1H), 7.44-7.26(m, 2H), 7.69-7.46(m, 3H), 7.91-7.78(m, 2H), 9.15(s, 1H)。MS(ESI +)m/z 508.2(M+H) +。
Embodiment 258
6-(the chloro-6-fluorophenyl of 2-)-2-{[2-(propyl group is amino)-2,3-dihydro-1H-indenes-5-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 258A
N 2-propyl group-2,3-dihydro-1H-indenes-2,5-diamines
As described in embodiment 226A, embodiment 226B and embodiment 226C, prepare title compound, with third-1-amine, substitute diethylamine.MS m/z: 191(M+H) +。 1H NMR(400 MHz, DMSO-d 6): δ 6.78(d, J=8.0 Hz, 1 H), 6.38(s, 1 H), 6.33-6.30(m, 1 H), 4.72(s, 2 H), 3.39(dt, J=13.6, 7.2 Hz, 1 H), 2.87(dt, J=14.8, 7.2 Hz, 2 H), 2.45-2.42(m, 4 H), 1.45-1.36(m, 2 H), 0.87(t, J=7.2 Hz, 3 H)。
Embodiment 258B
6-(the chloro-6-fluorophenyl of 2-)-2-{[2-(propyl group is amino)-2,3-dihydro-1H-indenes-5-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 123B, prepare title compound, with embodiment 95C and embodiment 258A difference alternate embodiment 123A and 4-(4-methylpiperazine-1-yl) aniline.Carry out aqueous solution processing, then carry out HPLC purifying. 1H NMR(500 MHz, CD 3OD)δ 1.06(t, J=7.4 Hz, 3H), 1.81-1.69(m, 2H), 3.24-3.01(m, 4H), 3.56-3.38(m, 2H), 4.18-4.08(m, 1H), 7.07(s, 1H), 7.47-7.26(m, 2H), 7.70-7.45(m, 3H), 7.92-7.74(m, 2H), 9.13(s, 1H)。MS(ESI +)m/z 504.2(M+H) +。
Embodiment 259
6-(the chloro-6-fluorophenyl of 2-)-2-{[2-(pyrrolidin-1-yl)-2,3-dihydro-1H-indenes-5-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 259A
2-(pyrrolidin-1-yl)-2,3-dihydro-1H-indenes-5-amine
As described in embodiment 226A, embodiment 226B and embodiment 226C, prepare title compound, with tetramethyleneimine, substitute diethylamine.MS m/z: 203(M+H) +。 1H NMR(400 MHz, CDCl 3): δ 6.95(d, J=8.0 Hz, 1 H), 6.54(s, 1 H), 6.48(dd, J=8.0, 2.0 Hz, 1 H), 3.53(s, 2 H), 3.03-2.97(m, 3 H), 2.96-2.92(m, 2 H), 2.61-2.57(m, 4 H), 1.86-1.80(m, 4 H)。
Embodiment 259B
6-(the chloro-6-fluorophenyl of 2-)-2-{[2-(pyrrolidin-1-yl)-2,3-dihydro-1H-indenes-5-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 123B, prepare title compound, with embodiment 95C and embodiment 259A difference alternate embodiment 123A and 4-(4-methylpiperazine-1-yl) aniline.Carry out aqueous solution processing, then carry out HPLC purifying. 1H NMR(500 MHz, CD 3OD)δ 2.12-2.02(m, 2H), 2.24-2.10(m, 2H), 3.25-3.15(m, 4H), 3.56-3.38(m, 2H), 3.72(bs, 2H), 4.21-4.11(m, 1H), 7.09-7.04(m, 1H), 7.35-7.28(m, 1H), 7.39(t, J=8.8 Hz, 1H), 7.68-7.45(m, 3H), 7.91-7.74(m, 2H), 9.11(s, 1H)。MS(ESI +)m/z 516.2(M+H) +。
Embodiment 260
6-(2-chloro-phenyl-)-2-[(4-{4-[2-(dimethylamino) ethyl] piperazine-1-yl } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 260A
N, N-dimethyl-2-(4-(4-nitrophenyl) piperazine-1-yl) ethamine
As described in embodiment 183A, prepare title compound, with N, N-dimethyl-2-(piperazine-1-yl) ethamine substitutes two (2-methoxy ethyl) amine.MS(ESI +)m/e 279.2(M + H) +。
Embodiment 260B
4-(4-(2-(dimethylamino) ethyl) piperazine-1-yl) aniline
As described in embodiment 183B, prepare title compound, with embodiment 260A alternate embodiment 183A.
Embodiment 260C
6-(2-chloro-phenyl-)-2-[(4-{4-[2-(dimethylamino) ethyl] piperazine-1-yl } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 183C, prepare title compound, with embodiment 260B alternate embodiment 183B. 1H NMR(400 MHz, DMSO-d 6) δ 10.67(br s, 1H), 9.08(s, 1H), 7.64(m, 7H), 7.07(m, 3H), 3.61(m, 8H), 3.41(m, 4H), 2.85(s, 6H)。MS(ESI +)m/e 544.2(M + H) +。
Embodiment 261
6-(2-chloro-phenyl-)-2-[(4-{[3-(dimethylamino) propyl group] (methyl) amino } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 261A
N 1, N 1, N 3-trimethylammonium-N 3-(4-nitrophenyl) propane-1,3-diamines
As described in embodiment 183A, prepare title compound, use N 1, N 1, N 3-trimethyl propane-1,3-diamines substitutes two (2-methoxy ethyl) amine.MS(ESI +)m/e 238.1(M + H) +。
Embodiment 261B
N 1-(3-(dimethylamino) propyl group)-N 1-methylbenzene-Isosorbide-5-Nitrae-diamines
As described in embodiment 183B, prepare title compound, with embodiment 261A alternate embodiment 183A.
Embodiment 261C
6-(2-chloro-phenyl-)-2-[(4-{[3-(dimethylamino) propyl group] (methyl) amino } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 183C, prepare title compound, with embodiment 261B alternate embodiment 183B. 1H NMR(400 MHz, DMSO-d 6) δ 10.59(br s, 1H), 9.05(s, 1H), 7.65(m, 7H), 7.07(s, 1H), 6.83(m, 2H), 3.38(m, 2H), 3.10(m, 2H), 2.91(s, 3H), 2.78(s, 6H), 1.88(m, 2H)。MS(ESI +)m/e 503.2(M + H) +。
Embodiment 262
6-(2-chloro-phenyl-)-2-[(4-{[2-(dimethylamino) ethyl] (ethyl) amino } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 262A
N 1-ethyl-N 2, N 2-dimethyl-N 1-(4-nitrophenyl) ethane-1,2-diamines
As described in embodiment 183A, prepare title compound, use N 1-ethyl-N 2, N 2-dimethyl ethane-1,2-diamines substitutes two (2-methoxy ethyl) amine.MS(ESI +)m/e 238.2(M + H) +。
Embodiment 262B
N 1-(2-(dimethylamino) ethyl)-N 1-ethylbenzene-Isosorbide-5-Nitrae-diamines
As described in embodiment 183B, prepare title compound, with embodiment 262A alternate embodiment 183A.
Embodiment 262C
6-(2-chloro-phenyl-)-2-[(4-{[2-(dimethylamino) ethyl] (ethyl) amino } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 183C, prepare title compound, with embodiment 262B alternate embodiment 183B. 1H NMR(400 MHz, DMSO-d 6) δ 10.61(br, 1H), 9.06(s, 1H), 7.72(m, 3H), 7.57(m, 4H), 7.07(s, 1H), 6.86(m, 2H), 3.59(m, 2H), 3.39(m, 2H), 3.24(m, 2H), 2.87(s, 6H), 1.08(m, 3H)。MS(ESI +)m/e 503.1(M + H) +。
Embodiment 263
6-(2-chloro-phenyl-)-2-[(4-{[2-(dimethylamino) ethyl] (methyl) amino } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 263A
N 1, N 1, N 2-trimethylammonium-N 2-(4-nitrophenyl) ethane-1,2-diamines
As described in embodiment 183A, prepare title compound, use N 1, N 1, N 2-trimethylammonium ethane-1,2-diamines substitutes two (2-methoxy ethyl) amine.MS(ESI +)m/e 224.1(M + H) +。
Embodiment 263B
N 1-(2-(dimethylamino) ethyl)-N 1-methylbenzene-Isosorbide-5-Nitrae-diamines
As described in embodiment 183B, prepare title compound, with embodiment 263A alternate embodiment 183A.
Embodiment 263C
6-(2-chloro-phenyl-)-2-[(4-{[2-(dimethylamino) ethyl] (methyl) amino } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 183C, prepare title compound, with embodiment 263B alternate embodiment 183B. 1H NMR(400 MHz, DMSO-d 6) δ 10.62(br s, 1H), 9.06(s, 1H), 7.73(m, 3H), 7.58(m, 4H), 7.07(s, 1H), 6.89(m,2H), 3.65(m, 2H), 3.26(m, 2H), 2.93(s, 3H), 2.86(s, 6H)。MS(ESI +)m/e 489.1(M + H) +。
Embodiment 264
6-(2-chloro-phenyl-)-2-(4-[(2S) and-2-(methoxymethyl) pyrrolidin-1-yl] phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 264A
(S)-2-(methoxymethyl) tetramethyleneimine
As described in embodiment 183A, prepare title compound, with (S)-2-(methoxymethyl) tetramethyleneimine, substitute two (2-methoxy ethyl) amine.MS(ESI +)m/e 237.1(M + H) +。
Embodiment 264B
(S)-4-(2-(methoxymethyl) pyrrolidin-1-yl) aniline
As described in embodiment 183B, prepare title compound, with embodiment 264A alternate embodiment 183A.
Embodiment 264C
6-(2-chloro-phenyl-)-2-(4-[(2S) and-2-(methoxymethyl) pyrrolidin-1-yl] phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 183C, prepare title compound, with embodiment 264B alternate embodiment 183B. 1H NMR(400 MHz, DMSO-d 6, 90o C) δ 10.12(br s, 1H), 9.01(s, 1H), 7.71(s, 1H), 7.67(m, 1H), 7.54(m, 5H), 7.02(s, 1H), 6.68(m, 2H), 3.87(m, 1H), 3.44(m, 2H), 3.30(s, 3H), 3.13(m, 2H), 1.98(m, 4H)。MS(ESI +)m/e 502.3(M + H) +。
Embodiment 265
6-(the chloro-6-fluorophenyl of 2-)-2-{[2'-(2-methylpropionyl)-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl] amino imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 241, prepare title compound, with isopropylformic acid, substitute acetic acid. 1H NMR(400 MHz, DMSO-d 6)δ 1.06-0.91(m, 10H), 3.12-2.92(m, 1H), 3.67-3.54(m, 2H), 4.90-4.74(m, 2H), 6.92-6.85(m, 1H), 7.12(d, J=1.8 Hz, 1H), 7.76-7.47(m, 5H), 7.83-7.77(m, 1H), 9.14(s, 1H), 10.79(bs, 1H)。MS(ESI +)m/z 558.2(M+H) +。
Embodiment 266
6-(the chloro-6-fluorophenyl of 2-)-2-{[2'-(2,2-dimethyl propylene acyl group)-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl] amino imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 241, prepare title compound, with trimethylacetic acid, substitute acetic acid. 1H NMR(400 MHz, DMSO-d 6)δ 1.12-0.90(m, 4H), 1.24(s, 9H), 3.64(bs, 2H), 4.87(bs, 2H), 6.90-6.83(m, 1H), 7.12(d, J=1.8 Hz, 1H), 7.75-7.48(m, 5H), 7.77(d, J=1.8 Hz, 1H), 9.14(s, 1H), 10.75(bs, 1H)。MS(ESI +)m/z 572.2(M+H) +。
Embodiment 267
6-(the chloro-6-fluorophenyl of 2-)-2-{[2'-(cyclopentylcarbonyl)-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl] amino imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 241, prepare title compound, with cyclopentanecarboxylic acid, substitute acetic acid. 1H NMR(400 MHz, DMSO-d 6)δ 1.04-0.94(m, 4H), 1.81-1.52(m, 8H), 3.20-3.02(m, 1H), 3.64-3.57(m, 2H), 4.87-4.77(m, 2H), 6.90-6.88(m, 1H), 7.12(s, 1H), 7.75-7.47(m, 5H), 7.86-7.72(m, 1H), 9.14(s, 1H), 10.80(bs, 1H)。MS(ESI +)m/z 584.2(M+H) +。
Embodiment 268
6-(2-chloro-phenyl-)-2-[(4-{[2-(1H-imidazol-4 yl) ethyl] amino } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 268A
N-(2-(1H-imidazol-4 yl) ethyl)-4-N-methyl-p-nitroaniline
As described in embodiment 183A, prepare title compound, with 2-(1H-imidazol-4 yl) ethamine, substitute two (2-methoxy ethyl) amine.MS(ESI +)m/e233.2(M + H) +。
Embodiment 268B
N 1-(2-(1H-imidazol-4 yl) ethyl) benzene-Isosorbide-5-Nitrae-diamines
As described in embodiment 183B, prepare title compound, with embodiment 268A alternate embodiment 183A.
Embodiment 268C
6-(2-chloro-phenyl-)-2-[(4-{[2-(1H-imidazol-4 yl) ethyl] amino } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 183C, prepare title compound, with embodiment 268B alternate embodiment 183B. 1H NMR(400 MHz, DMSO-d 6, 90o C) δ 10.10(br s, 1H), 9.01(s, 1H), 8.88(s, 1H), 7.66(m, 2H), 7.53(m, 5H), 7.42(s, 1H), 7.02 9s, 1H), 6.67(d, 2H), 3.39(t, 2H), 2.95(t, 2H)。MS(ESI +)m/e 498.2(M + H) +。
Embodiment 269
6-(2-chloro-phenyl-)-2-[(4-{[3-(1H-imidazoles-1-yl) propyl group] amino } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 269A
N-(3-(1H-imidazoles-1-yl) propyl group)-4-N-methyl-p-nitroaniline
As described in embodiment 183A, prepare title compound, with 3-(1H-imidazoles-1-yl) third-1-amine, substitute two (2-methoxy ethyl) amine.MS(ESI +)m/e 247.1(M + H) +。
Embodiment 269B
As described in embodiment 183B, prepare title compound, with embodiment 269A alternate embodiment 183A.
Embodiment 269C
6-(2-chloro-phenyl-)-2-[(4-{[3-(1H-imidazoles-1-yl) propyl group] amino } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 183C, prepare title compound, with embodiment 269B alternate embodiment 183B. 1H NMR(400 MHz, DMSO-d 6, 90o C) δ 10.10(br s, 1H), 9.00(s, 1H), 7.67(m, 3H), 7.56(m,7H), 7.02(s, 1H), 6.63(m, 2H), 4.33(t, 2H), 3.10(m, 2H), 2.14(t, 2H)。MS(ESI +)m/e 512.2(M + H) +。
Embodiment 270
6-(2-chloro-phenyl-)-2-{[4-(thiomorpholine-4-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 270A
4-(4-nitrophenyl) thiomorpholine
As described in embodiment 183A, prepare title compound, with thiomorpholine, substitute two (2-methoxy ethyl) amine.MS(ESI +)m/e 225.1(M + H) +。
Embodiment 270B
4-thiomorpholine is for aniline
As described in embodiment 183B, prepare title compound, with embodiment 270A alternate embodiment 183A.
Embodiment 270C
6-(2-chloro-phenyl-)-2-{[4-(thiomorpholine-4-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 183C, prepare title compound, with embodiment 270B alternate embodiment 183B. 1H NMR(400 MHz, DMSO-d 6) δ 10.67(br s, 1H), 9.08(s, 1H), 7.64(m, 7H), 7.07(m, 3H), 3.54(m, 4H), 2.74(m, 4H)。MS(ESI +)m/e 490.2(M + H) +。
Embodiment 271
6-(2-chloro-phenyl-)-2-[(4-{ third-2-base [2-(third-2-base is amino) ethyl] amino } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 271A
N 1, N 2-di-isopropyl-N 1-(4-nitrophenyl) ethane-1,2-diamines
As described in embodiment 183A, prepare title compound, use N 1, N 2-di-isopropyl ethane-1,2-diamines substitutes two (2-methoxy ethyl) amine.MS(ESI +)m/e 266.2(M + H) +。
Embodiment 271B
N 1-sec.-propyl-N 1-(2-(isopropylamine base) ethyl) benzene-Isosorbide-5-Nitrae-diamines
As described in embodiment 183B, prepare title compound, with embodiment 271A alternate embodiment 183A.
Embodiment 271C
6-(2-chloro-phenyl-)-2-[(4-{ third-2-base [2-(third-2-base is amino) ethyl] amino } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 183C, prepare title compound, with embodiment 271B alternate embodiment 183B. 1H NMR(500 MHz, DMSO-d 6) δ 10.55(br s, 1H), 9.05(s, 1H), 7.65(m, 7H), 7.06(s, 1H), 6.69(m, 2H), 3.44(m, 4H), 3.23(m, 2H)。MS(ESI +)m/e 531.2(M + H) +。
Embodiment 272
1-(4-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } phenyl) piperidines-3-methane amide
Embodiment 272A
1-(4-nitrophenyl) piperidines-3-methane amide
As described in embodiment 183A, prepare title compound, with piperidines-3-methane amide, substitute two (2-methoxy ethyl) amine.MS(ESI +)m/e 250.2(M + H) +。
Embodiment 272B
1-(4-aminophenyl) piperidines-3-methane amide
As described in embodiment 183B, prepare title compound, with embodiment 272A alternate embodiment 183A.
Embodiment 272C
1-(4-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } phenyl) piperidines-3-methane amide
As described in embodiment 183C, prepare title compound, with embodiment 272B alternate embodiment 183B. 1H NMR(400 MHz, DMSO-d 6, 90o C) δ 10.29 9(br s, 1H), 9.05(s, 1H), 7.68(m, 4H), 7.54(m, 3H), 7.09(m, 2H), 7.03(s, 1H), 3.65(m, 2H), 2.90(m, 2H), 2.54(m, 1H), 1.71(m, 4H)。MS(ESI +)m/e 515.2(M + H) +。
Embodiment 273
6-(2,6-dichlorophenyl)-2-[(4-{[2-(1-methylpyrrolidin-2-yl) ethyl] amino } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 150, prepare title compound (0.07 g), use N 1-(2-(1-methylpyrrolidin-2-yl) ethyl) benzene-Isosorbide-5-Nitrae-diamines substitutes 1,1,2-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-6-amine.With Analogix 280 (SF 12-24 post), carry out chromatographic separation, use 5% ethanol/methylene (containing a small amount of ammonium hydroxide) wash-out 30 minutes. 1H NMR(500 MHz, DMSO-d 6) δ 1.40-1.56(m, 2 H)1.55-1.74(m, 2 H)1.82-1.97(m, 2 H)2.00-2.17(m, 2 H)2.17-2.27(m, 3 H)2.83-3.14(m, 3 H)5.38-5.68(m, 1 H)6.47-6.72(m, 2 H)7.09(s, 1 H)7.37(d, J=8.24 Hz, 1 H)7.50-7.68(m, 3 H)7.69-7.84(m, 3 H)9.05(s, 1 H)10.57(s, 1 H)。MS(ESI +)m/z 549.2(M+H) +。
Embodiment 274
6-(2,6-dichlorophenyl)-2-{[2'-(2-methylpropionyl)-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl] amino imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 207, prepare title compound (0.075 g), with isobutyryl chloride, substitute diacetyl oxide.Crude product is ground together with ethyl acetate, title compound is provided. 1H NMR(500 MHz, DMSO-d 6) δ 0.77-1.14(m, 10 H)2.91-3.17(m, 1 H)3.49-3.75(m, 2 H)4.61-4.99(m, 2 H)6.89(s, 1 H)7.13(s, 1 H)7.40-8.06(m, 6 H)9.16(s, 1 H)10.84(s, 1 H)。MS(ESI +)m/z 574.2(M+H) +。
Embodiment 275
2-{[2'-(cyclopropyl carbonyl)-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl] amino-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 207, prepare title compound (0.065 g), with cyclopropane carbonyl chlorine, substitute diacetyl oxide.Crude product is ground together with ethyl acetate, title compound is provided. 1H NMR(500 MHz, DMSO-d 6) δ 0.74(d, 4 H)1.00(d, 4 H)2.13(d, 1 H)3.46-3.92(m, 2 H)4.51-5.20(m, 2 H)6.90(d, J=1.22 Hz, 1 H)7.12(s, 1 H)7.42-8.08(m, 6 H)9.16(s, 1 H)10.84(s, 1 H)。MS(ESI +)m/z 572.2(M+H) +。
Embodiment 276
6-(2,6-dichlorophenyl)-2-{[2'-(2,2-dimethyl propylene acyl group)-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl] amino imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 207, prepare title compound (0.055 g), with valeryl chlorine, substitute diacetyl oxide.With Analogix 280 (SF 12-24 post), carry out chromatographic separation, use 50% to 100% ethyl acetate/hexane gradient elution 30 minutes, title compound is provided. 1H NMR(500 MHz, DMSO-d 6) δ 0.87-1.09(m, 4 H)1.15-1.33(m, 9 H)3.62(d, 2 H)4.86(d, 2 H)6.87(d, J=6.71 Hz, 1 H)7.13(s, 1 H)7.48-7.72(m, 3 H)7.70-7.86(m, 3 H)9.15(s, 1 H)10.61-10.98(m, J=10.99 Hz, 1 H)。MS(ESI +)m/z 588.3(M+H) +。
Embodiment 277
6-(the chloro-6-fluorophenyl of 2-)-2-(5,6,7,8-tetrahydrochysene-1,6-naphthyridines-3-base is amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 277A
3-[4-(the fluoro-phenyl of the chloro-6-of 2-)-5-oxo-4,5-dihydro-3,4,7,9,9b-pentaaza-cyclopenta [a] naphthalene-8-base is amino]-7,8-dihydro-5H-[1,6] naphthyridines-6-formic acid tertiary butyl ester
By embodiment 95C (70.0 mg, 0.193 mmol) and metachloroperbenzoic acid (52.0 mg, 0.232 mmol) at CH 2cl 2mixture in (2 mL) stirs 20 minutes.By 3-amino-7,8-dihydro-1,6-naphthyridines-6 (5H)-formic acid tertiary butyl ester (57.9 mg, 0.232 mmol) joins in this reaction mixture.After 5 hours, by ethyl acetate, dilute this reaction mixture, use saturated NaHCO 3the aqueous solution and salt water washing.By organic layer MgSO 4dry, filter, concentrated, purifying on 12 g posts, is used ISCO Companion flash chromatographic system, with eluent ethyl acetate, provides title compound.
Embodiment 277B
6-(the chloro-6-fluorophenyl of 2-)-2-(5,6,7,8-tetrahydrochysene-1,6-naphthyridines-3-base is amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
By embodiment 277A (54.6 mg, 0.097 mmol) and trifluoroacetic acid (0.075 mL, 0.970 mmol) at CH 2cl 2mixture in (3 mL) stirs and spends the night.Cross filter solid, use CH 2cl 2rinse, be dried, the trifluoroacetate of title compound is provided. 1H NMR(400 MHz, CD 3OD)δ 3.29-3.26(m, 2H), 3.68(t, J=6.4 Hz, 2H), 4.55(s, 2H), 7.11(d, J=1.9 Hz, 1H), 7.44-7.35(m, 1H), 7.56-7.53(m, 1H), 7.66-7.60(m, 1H), 7.91(d, J=1.9 Hz, 1H), 8.38(bs, 1H), 8.93(bs, 1H), 9.26(s, 1H)。MS(ESI +)m/z 463.2(M+H) +。
Embodiment 278
6-(2-chloro-3-hydroxyl phenyl)-2-(2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-base amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 278A
The chloro-3-oil of mirbane of 1-(allyloxy)-2-
In the acetone soln of the chloro-3-nitrophenols of 2-(1.5 g, 8.64 mmol), add salt of wormwood (1.194 g, 8.64 mmol).After 5 minutes, add allyl bromide 98 (0.823 mL, 9.51 mmol), and this solution is heated to reflux spends the night.This reaction mixture is cooling, filter, concentrated.With Analogix 280 (SF 40-80 post), carry out chromatographic separation, use 0% to 10% ethyl acetate/hexane gradient elution 30 minutes, title compound is provided.MS(DCI +)m/z 231.1(M+NH 4) +。
Embodiment 278B
3-(allyloxy)-2-chloroaniline
In ethyl acetate (60 mL) solution of embodiment 278A (2 g, 10.35 mmol), add tin chloride (II) dihydrate (8.18 g, 36.2 mmol), and by this mixture 65 ℃ of heated overnight.This reaction mixture is cooled to room temperature, with 100 mL ethyl acetate dilutions, adds 1M Na 2cO 3the aqueous solution, until stop precipitation.By Celite pad, cross filter solid.Filter bed is suspended in ethyl acetate, stirs several minutes, and use ethyl acetate rinse.Use saturated Na 2cO 3the aqueous solution, water and salt solution wash filtrate, use MgSO 4dry, filter, concentrated.With Analogix 280 (SF 40-80 post), carry out chromatographic separation, use 0% to 5% ethanol/methylene gradient elution 30 minutes, title compound is provided.MS(DCI +)m/z 164.1(M+H) +。
Embodiment 278C
The chloro-3-isocyanato of 1-(allyloxy)-2-benzene
To triphosgene (0.593 g, 1.999 mmol) in 40 mL toluene solutions, add at leisure triethylamine (1.290 mL, 9.26 mmol) and 3-(allyloxy)-2-chloroaniline (1 g, 5.45 mmol) (being dissolved in 10 mL toluene).This mixture is heated to 70 ℃ and spends the night, filter, concentrated.With 100 ml ethyl acetate dilution resistatess, use saturated NaHCO 3the aqueous solution, water and salt water washing organism, use MgSO 4dry, filter, concentrated.Title compound just need not be further purified and in next step, use rapidly.
Embodiment 278D
3-(3-(allyloxy)-2-chloro-phenyl-)-7-(methylthio group) Kui Linpyrimido quinoline [4,5-d] pyrimidine-2,4 (1H, 3H)-diketone
As described in embodiment 1A, prepare title compound (1.36 g), with embodiment 278C, substitute the chloro-2-isocyanato of 1-benzene.With Analogix 280 (SF 40-80 post), carry out chromatographic separation, use 20% to 60% ethyl acetate/hexane gradient elution 30 minutes, title compound is provided.MS(ESI +)m/z 377.0(M+H) +。
Embodiment 278E
3-(3-(allyloxy)-2-chloro-phenyl-) the chloro-7-of-2-(methylthio group) Kui Linpyrimido quinoline [4,5-d] pyrimidine-4 (3H)-one
As described in embodiment 1B, prepare title compound (1.7 g), with embodiment 278D alternate embodiment 1A.MS(ESI +)m/z 361.19(M+H) +。
Embodiment 278F
3-(3-(allyloxy)-2-chloro-phenyl-)-2-(2,2-dimethoxy-ethyl is amino)-7-(methylthio group) Kui Linpyrimido quinoline [4,5-d] pyrimidine-4 (3H)-one
As described in embodiment 1C, prepare title compound (1.3 g), with embodiment 278E alternate embodiment 1B.MS(ESI +)m/z 464.4(M+H) +。
Embodiment 278G
The chloro-3-of 6-[2-(third-2-alkene-1-base oxygen base) phenyl]-2-(methyl sulfenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 1D, prepare title compound (1 g), with embodiment 278F alternate embodiment 1C.With Analogix 280 (SF 40-120 post), carry out chromatographic separation, use 40% to 100% ethyl acetate/hexane gradient elution 30 minutes, title compound is provided.MS(ESI +)m/z 400.22(M+H) +。
Embodiment 278H
7'-(the chloro-3-of 6-[2-(third-2-alkene-1-base oxygen base) phenyl]-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also } amino)-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-2'(3'H)-formic acid tertiary butyl ester
As described in embodiment 109A, prepare title compound (0.2g), with embodiment 278G alternate embodiment 55D.Crude product just enters next step without purifying.MS(ESI +)m/z 625.85(M+H) +。
Embodiment 278I
The chloro-3-of 6-[2-(third-2-alkene-1-base oxygen base) phenyl]-2-(2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-base amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 109B, prepare title compound (0.2 g), with embodiment 278H alternate embodiment 109A, but dilute this reaction by ethyl acetate, use saturated NaHCO 3the aqueous solution, water and salt water washing organism, use MgSO 4dry, filter, concentrate, the free alkali of title compound is provided.MS(ESI +)m/z 526.2(M+H) +。
Embodiment 278J
6-(2-chloro-3-hydroxyl phenyl)-2-(2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-base amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 54G, prepare title compound (0.025 g), with embodiment 278I alternate embodiment 54F.Use preparative HPLC to carry out purifying (on Phenomenex Luna C8 (2) 5 μ m 100 AXIA posts (30mm * 75mm)).Use the gradient of acetonitrile (A) and 0.1% trifluoroacetic acid/water (B), flow velocity 50 mL/min (0-0.5 min, 10% A; 0.5-7.0 min linear gradient, 10-95% A; 7.0-10.0 min, 95% A; 10.0-12.0 min linear gradient, 95-10% A).Tfa salt is dissolved in methyl alcohol, with excessive 2M HCl/ diethyl ether, processes, stir, until start to form solid.With ether, dilute this mixture, stir 10 minutes, filter, title compound is provided.MS(ESI+)m/z 378.2(M+H)+。 1H NMR(300 MHz, DMSO-d 6) δ 1.11(d, J=2.37 Hz, 4 H)3.28(s, 2 H)4.46(s, 2 H)6.86-7.20(m, 4 H)7.32(t, J=8.14 Hz, 1 H)7.75(d, J=32.21 Hz, 3 H)9.12(s, 1 H)9.38(s, 2 H)10.55(s, 1 H)10.78(s, 1 H)。MS(ESI +)m/z 457.1(M+H) +。
Embodiment 279
2-(2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-base amino)-6-(4-hydroxy-2-methyl phenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 279A
4-(allyloxy)-1-isocyanato-2-methylbenzene
As described in embodiment 278C, prepare title compound (0.075 g), with 4-(allyloxy)-2-aminotoluene alternate embodiment 278B, and without purifying just for next step.
Embodiment 279B
3-(4-(allyloxy)-2-aminomethyl phenyl)-7-(methylthio group) Kui Linpyrimido quinoline [4,5-d] pyrimidine-2,4 (1H, 3H)-diketone
As described in embodiment 1A, prepare title compound (1.7 g), with embodiment 279A, substitute the chloro-2-isocyanato of 1-benzene.This compound without purifying just in next step use.MS(ESI +)m/z 357.19(M+H) +。
Embodiment 279C
3-(4-(allyloxy)-2-aminomethyl phenyl) the chloro-7-of-2-(methylthio group) Kui Linpyrimido quinoline [4,5-d] pyrimidine-4 (3H)-one
As described in embodiment 1B, prepare title compound (1.7 g), with embodiment 279B alternate embodiment 1A.This compound without purifying just in next step use.MS(ESI +)m/z 375.11(M+H) +。
Embodiment 279D
3-(4-(allyloxy)-2-aminomethyl phenyl)-2-(2,2-dimethoxy-ethyl is amino)-7-(methylthio group) Kui Linpyrimido quinoline [4,5-d] pyrimidine-4 (3H)-one
As described in embodiment 1C, prepare title compound (1.5 g), with embodiment 279C alternate embodiment 1B.MS(ESI +)m/z 444.4(M+H) +。
Embodiment 279E
6-[2-methyl-4-(third-2-alkene-1-base oxygen base) phenyl]-2-(methyl sulfenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 1D, prepare title compound (1.3 g), with embodiment 279D alternate embodiment 1C.With Analogix 280 (SF 40-120 post), carry out chromatographic separation, use 40% to 100% ethyl acetate/hexane gradient elution 30 minutes, title compound is provided.MS(ESI +)m/z 380.33(M+H) +。
Embodiment 279F
7'-(6-[2-methyl-4-(third-2-alkene-1-base oxygen base) phenyl]-5-oxo-5,6-glyoxalidine also [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base } amino)-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-2'(3'H)-formic acid tertiary butyl ester
As described in embodiment 109A, prepare title compound (0.085g), with embodiment 279E alternate embodiment 55D.Crude product just enters next step without purifying.MS(ESI +)m/z 625.85(M+H) +。
Embodiment 279G
2-(2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-base amino)-6-(4-hydroxy-2-methyl phenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 54G, prepare title compound (0.076 g), with embodiment 279F alternate embodiment 54F.Use preparative HPLC to carry out purifying (on Phenomenex Luna C8 (2) 5 μ m 100 AXIA posts (30mm * 75mm)).Use the gradient of acetonitrile (A) and 0.1% trifluoroacetic acid/water (B), flow velocity 50 mL/min (0-0.5 min, 10% A; 0.5-7.0 min linear gradient, 10-95% A; 7.0-10.0 min, 95% A; 10.0-12.0 min linear gradient, 95-10% A).Tfa salt is dissolved in methyl alcohol, with excessive 2M HCl/ diethyl ether, processes, stir, until start to form solid.With ether, dilute this mixture, stir 10 minutes, filter, title compound is provided. 1H NMR(300 MHz, DMSO-d 6) δ 0.97-1.27(m, 4 H)1.82-2.07(m, 3 H)3.13-3.40(m, 2 H)4.33-4.58(m, 2 H)6.66-6.82(m, 2 H)6.86-6.96(m, 1 H)7.04-7.13(m, 2 H)7.51-7.91(m, 3 H)9.10(s, 1 H)9.54(s, 2 H)10.73(s, 2 H)。MS(ESI +)m/z 466.19(M+H) +。
Embodiment 280
6-(the chloro-6-fluorophenyl of 2-)-2-{[2-(2,2-, bis-fluoro ethyls)-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 280A
2-(2,2-, bis-fluoro ethyls)-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-amine
As described in embodiment 224B, prepare title compound, with 4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-amine alternate embodiment 224A, and use the K of 2.5 equivalents 2cO 3.
Embodiment 280B
6-(the chloro-6-fluorophenyl of 2-)-2-{[2-(2,2-, bis-fluoro ethyls)-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 123B, prepare title compound, with embodiment 95C and embodiment 280A difference alternate embodiment 123A and 4-(4-methylpiperazine-1-yl) aniline.Carry out aqueous solution processing, then carry out HPLC purifying (referring to the HPLC scheme of embodiment 241). 1H NMR(400 MHz, CD 3OD)δ 1.48(s, 6H), 3.43(s, 2H), 3.75(td, J=14.7, 3.8 Hz, 2H), 4.49(s, 2H), 6.48(tt, J=54.0, 3.9 Hz, 1H), 7.09(d, J=1.8 Hz, 1H), 7.39(td, J=9.1, 1.2 Hz, 1H), 7.56-7.52(m, 2H), 7.66-7.60(m, 1H), 7.81-7.67(m, 2H), 7.87(s, 1H), 9.18(s, 1H)。MS(ESI +)m/z 554.2(M+H) +。
Embodiment 281
6-(the chloro-6-fluorophenyl of 2-)-2-{[2-(2-fluoro ethyl)-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 281A
2-(2-fluoro ethyl)-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-amine
As described in embodiment 224B, prepare title compound, with 4,4-dimethyl-1, the bromo-2-fluoroethane of 2,3,4-tetrahydroisoquinoline-7-amine and 1-is alternate embodiment 224A and the fluoro-2-iodoethane of 1,1-bis-respectively, and uses the K of 2.5 equivalents 2cO 3.
Embodiment 281B
6-(the chloro-6-fluorophenyl of 2-)-2-{[2-(2-fluoro ethyl)-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 123B, prepare title compound, with embodiment 95C and embodiment 281A difference alternate embodiment 123A and 4-(4-methylpiperazine-1-yl) aniline.Carry out aqueous solution processing, then carry out HPLC purifying (referring to the HPLC scheme of embodiment 241). 1H NMR(400 MHz, CD 3OD)δ 1.50(s, 6H), 3.56(bs, 2H), 3.88-3.67(m, 2H), 4.62(bs, 2H), 5.06-4.93(m, 2H), 7.08(d, J=1.8 Hz, 1H), 7.43-7.33(m, 1H), 7.68-7.47(m, 3H), 7.85-7.71(m, 2H), 7.88(s, 1H), 9.18(s, 1H)。MS(ESI +)m/z 536.2(M+H) +。
Embodiment 282
2-{[4-(Isosorbide-5-Nitrae '-Lian piperidines-1'-yl) phenyl] amino-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 150, prepare title compound (0.075 g), and use 4-(Isosorbide-5-Nitrae '-Lian piperidines-1'-yl) alternative 1,1, the 2-of aniline trimethylammonium-1,2,3,4-tetrahydroisoquinoline-6-amine.Crude product is ground together with ethyl acetate, title compound is provided. 1H NMR(300 MHz, DMSO-d 6) δ 1.49(d, 9 H)1.81(d, 2 H)2.32(d, 1 H)2.56-2.75(m, 3 H)3.70(d, 2 H)7.00(d, J=8.14 Hz, 2 H)7.10(d, J=1.70 Hz, 1 H)7.47-7.87(m, 6 H)9.09(s, 1 H)10.69(s, 1 H)。MS(ESI +)m/z 589.2(M+H) +。
Embodiment 283
6-(2,6-dichlorophenyl)-2-(4-[(3R) and-3-(dimethylamino) pyrrolidin-1-yl] phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 150, prepare title compound (0.08 g), with (R)-1-(4-aminophenyl)-N, N-dimethyl pyrrolidine-3-amine substitutes 1,1,2-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-6-amine.With Analogix 280 (SF 12-24 post), carry out chromatographic separation, use 4% ethanol/methylene (containing a small amount of ammonium hydroxide) wash-out 30 minutes.Purifying substance is dissolved in methyl alcohol, with excessive 2M HCl/ diethyl ether, processes, stir, until start to form solid.With ether, dilute this mixture, stir 10 minutes, filter, title compound is provided. 1H NMR(300 MHz, DMSO-d 6) δ 2.33(d, 2 H)2.83(d, 6 H)3.27(d, 1 H)3.59(d, 4 H)6.72(d, J=8.82 Hz, 2 H)7.10(d, J=1.70 Hz, 1 H)7.44-7.96(m, 6 H)9.08(s, 1 H)10.66(s, 1 H)10.90(s, 1 H)。MS(ESI +)m/z 535.2(M+H) +。
Embodiment 284
6-(2,6-dichlorophenyl)-2-[(4-{[2-(dimethylamino) ethyl] amino } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 150, prepare title compound (0.05 g), with the chloro-4-of 3-(4-methylpiperazine-1-yl) aniline, substitute 1,1,2-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-6-amine.With Analogix 280 (SF 12-24 post), carry out chromatographic separation, use 4% ethanol/methylene (containing a small amount of ammonium hydroxide) wash-out 30 minutes.Purifying substance is dissolved in methyl alcohol, with excessive 2M HCl/ diethyl ether, processes, stir, until start to form solid.With ether, dilute this mixture, stir 10 minutes, filter, title compound is provided. 1H NMR(300 MHz, DMSO-d 6) δ 2.80(d, 6 H)3.23(d, 2 H)3.45(d, 2 H)6.75(d, J=8.82 Hz, 2 H)7.10(d, J=1.70 Hz, 1 H)7.46(s, 1 H)7.53-7.72(m, 3 H)7.69-7.84(m, 3 H)9.08(s, 1 H)10.63(s, 1 H)。MS(ESI +)m/z 509.2(M+H) +。
Embodiment 285
2-{[2'-(cyclopropyl alkylsulfonyl)-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl] amino-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 206, prepare title compound (0.048 g), by ring the third SULPHURYL CHLORIDE, substitute methylsulfonyl chloride.With Analogix 280 (SF 12-24 post), carry out chromatographic separation, use 40% to 100% ethyl acetate/hexane gradient elution 30 minutes. 1H NMR(300 MHz, DMSO-d 6) δ 0.95(d, 8 H)2.61(d, 1 H)3.39(d, 2 H)4.58(d, 2 H)6.88(d, J=8.33 Hz, 1 H)7.13(d, J=1.98 Hz, 1 H)7.46-7.99(m, 6 H)9.16(s, 1 H)10.83(s, 1 H)。MS(ESI +)m/z 608.2(M+H) +。
Embodiment 286
6-(2,6-dichlorophenyl)-2-{[2'-(third-2-base alkylsulfonyl)-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl] amino imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 206, prepare title compound (0.04 g), by propane-2-SULPHURYL CHLORIDE, substitute methylsulfonyl chloride.With Analogix 280 (SF 12-24 post), carry out chromatographic separation, use 40% to 100% ethyl acetate/hexane gradient elution 30 minutes. 1H NMR(300 MHz, DMSO-d 6) δ 1.00(d, 4 H)1.25(d, 6 H)3.43(d, 2 H)4.57(d, 2 H)6.88(d, J=9.12 Hz, 1 H)7.13(d, J=1.98 Hz, 1 H)7.41-7.96(m, 6 H)9.15(s, 1 H)10.83(s, 1 H)。MS(ESI +)m/z 610.2(M+H) +。
Embodiment 287
6-(2,6-dichlorophenyl)-2-{[4-(1-methyl piperidine-4-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 150, prepare title compound (0.07 g), with 4-(1-methyl piperidine-4-yl) aniline, substitute 1,1,2-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-6-amine.With Analogix 280 (SF 12-24 post), carry out chromatographic separation, use 5% ethanol/methylene (containing a small amount of ammonium hydroxide) wash-out 30 minutes.Purifying substance is dissolved in methyl alcohol, with excessive 2M HCl/ diethyl ether, processes, stir, until start to form solid.With ether, dilute this mixture, stir 10 minutes, filter, title compound is provided. 1H NMR(300 MHz, DMSO-d 6) δ 1.94(d, 4 H)2.78(d, 4 H)2.97-3.17(m, 2 H)7.12(d, J=1.98 Hz, 1 H)7.21-7.40(m, 2 H)7.51-8.09(m, 6 H)9.16(s, 1 H)10.10(s, 1 H)10.87(s, 1 H)。MS(ESI +)m/z 520.3(M+H) +。
Embodiment 288
2-{[4-(2,7-diaza spiro [3.5] ninth of the ten Heavenly Stems-7-yl) phenyl] amino }-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 288A
7-(4-nitrophenyl)-2,7-diaza spiro [3.5] nonane-2-formic acid tertiary butyl ester
In the DMSO solution of the fluoro-4-oil of mirbane of 1-(0.155 mL, 1.458 mmol), add DIPEA (0.926 mL, 5.30 mmol), then add 2,7-diaza spiro [3.5] nonane-2-formic acid tertiary butyl ester (300 mg, 1.326 mmol).This reaction mixture is heated to 100 ℃ and spends the night, and be cooled to room temperature.With 75 mL shrends this reaction mixture that goes out, filter, wash with water, high vacuum dry, provides title compound.MS(ESI +)m/z 348.1(M+H) +。
Embodiment 288B
7-(4-aminophenyl)-2,7-diaza spiro [3.5] nonane-2-formic acid tertiary butyl ester
Embodiment 288A (350 mg, 1.007 mmol) and 49 mg 10% Pd/C are joined in 100 mL flasks, then add 5 mL methyl alcohol.Then make flask be full of hydrogen (utilizing sacculus to carry out vacuum cycle).Stir this reaction and spend the night, with methylene dichloride dilution, by diatomite filtration, concentrated, title compound is provided.MS(ESI +)m/z 318.4(M+H) +。
Embodiment 288C
7-(4-{[6-(2,6-dichlorophenyl)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } phenyl)-2,7-diaza spiro [3.5] nonane-2-formic acid tertiary butyl ester
As described in embodiment 109A, prepare title compound (0.12 g), the alternative 7'-amino-1'H-spiral shell of use embodiment 288B [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-2'(3'H)-formic acid tertiary butyl ester.With Analogix 280 (SF 12-24 post), carry out chromatographic separation, use 40% to 100% ethyl acetate/hexane gradient elution 30 minutes.MS(ESI +)m/z 647.35(M+H) +。
Embodiment 288D
2-{[4-(2,7-diaza spiro [3.5] ninth of the ten Heavenly Stems-7-yl) phenyl] amino }-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 109B, prepare title compound (0.11g), with embodiment 135A alternate embodiment 109A.Tfa salt is dissolved in methyl alcohol, with excessive 2M HCl/ diethyl ether, processes, stir, until start to form solid.With ether, dilute this mixture, stir 10 minutes, filter, title compound is provided. 1H NMR(300 MHz, DMSO-d 6) δ 2.01(d, 4 H)3.25(d, 4 H)3.80(d, 4 H)7.12(d, J=1.70 Hz, 1 H)7.26(s, 2 H)7.51-8.01(m, 6 H)8.90(s, 2 H)9.14(s, 1 H)10.80(s, 1 H)。MS(ESI +)m/z 547.2(M+H) +。
Embodiment 289
6-(2-chloro-phenyl-)-2-(4-[2-(trifluoromethyl) pyrrolidin-1-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 289A
1-(4-nitrophenyl)-2-(trifluoromethyl) tetramethyleneimine
As described in embodiment 183A, prepare title compound, with 2-(trifluoromethyl) tetramethyleneimine, substitute two (2-methoxy ethyl) amine.MS(ESI +)m/e 261.1(M + H) +。
Embodiment 289B
4-(2-(trifluoromethyl) pyrrolidin-1-yl) aniline
As described in embodiment 183B, prepare title compound, with embodiment 289A alternate embodiment 183A.
Embodiment 289C
6-(2-chloro-phenyl-)-2-(4-[2-(trifluoromethyl) pyrrolidin-1-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 183C, prepare title compound, with embodiment 289B alternate embodiment 183B. 1H NMR(400 MHz, DMSO-d 6, 90o C) δ 10.19(br s, 1H), 9.02(s, 1H), 7.59(m, 7H), 7.02(s, 1H), 6.85(d, 2H), 4.54(m, 1H), 3.61(M, 1H), 3.23(q, 1H), 2.11(m, 4H)。MS(ESI +)m/e 526.3(M + H) +。
Embodiment 290
6-(2-chloro-phenyl-)-2-{[4-(piperidin-4-yl oxygen base) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 203C, prepare title compound, with 4-(4-amino-benzene oxygen) piperidines-1-formic acid tertiary butyl ester alternate embodiment 203B. 1H NMR(500 MHz, DMSO-d 6, 90o C) δ 10.33(s, 1H), 9.06(s, 1H), 7.67(m, 4H), 7.55(m, 3H), 7.04(m, 3H), 4.51(m, 1H), 3.29(m, 2H), 3.13(m, 2H), 2.13(m, 2H), 1.90(m, 2H)。MS(ESI +)m/e 488.2(M + H) +。
Embodiment 291
6-(2-chloro-phenyl-)-2-{[4-(piperidin-4-ylmethyl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 203C, prepare title compound, with 4-(4-aminobenzyl) piperidines-1-formic acid tertiary butyl ester alternate embodiment 203B. 1H NMR(400 MHz, DMSO-d 6, 90o C) δ 10.39(s, 1H), 9.09(s, 1H), 7.70(m, 4H), 7.58(m, 3H), 7.22(d, 2H), 7.04(s, 1H), 3.27(m, 2H), 2.86(m, 2H), 2.58(d, 2H), 1.83(m, 3H), 1.39(m, 2H)。MS(ESI +)m/e 486.3(M + H) +。
Embodiment 292
6-(2-chloro-phenyl-)-2-{[4-(hexahydropyrrolo is [3,4-c] pyrroles-2 (1H)-yl also) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 292A
5-(4-nitrophenyl) hexahydropyrrolo is [3,4-c] pyrroles-2 (1H)-formic acid tertiary butyl ester also
As described in embodiment 183A, prepare title compound, with hexahydropyrrolo also [3,4-c] pyrroles-2 (1H)-formic acid tertiary butyl ester substitute two (2-methoxy ethyl) amine.
Embodiment 292B
5-(4-aminophenyl) hexahydropyrrolo is [3,4-c] pyrroles-2 (1H)-formic acid tertiary butyl ester also
As described in embodiment 183B, prepare title compound, with embodiment 292A alternate embodiment 183B.
Embodiment 292C
6-(2-chloro-phenyl-)-2-{[4-(hexahydropyrrolo is [3,4-c] pyrroles-2 (1H)-yl also) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 203C, prepare title compound, with embodiment 292B alternate embodiment 203B. 1H NMR(400 MHz, DMSO-d 6, 90o C) δ 10.18(br s, 1H), 9.02(s, 1H), 7.60(m, 7H), 7.02(s, 1H), 6.72(d, 2H), 3.51(m, 2H), 3.34(m, 4H), 3.10(m, 4H)。MS(ESI +)m/e 499.3(M + H) +。
Embodiment 293
1-(4-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } phenyl)-N-methyl Toluidrin
As described in embodiment 183C, prepare title compound, with N-(4-aminobenzyl) Toluidrin hydrochloride alternate embodiment 183B. 1H NMR(400 MHz, DMSO-d 6) δ 10.84(br s, 1H), 9.15(s, 1H), 7.86(m, 2H), 7.72(m, 1H), 7.60(m, 3H), 7.42(br d, 2H), 7.08(s, 1H), 6.93(m, 1H), 4.32(s, 2H), 2.59(d, 3H)。MS(ESI +)m/e 496.1(M + H) +。
Embodiment 294
4-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino }-N, N-diethyl benzene sulfonamide
As described in embodiment 183C, prepare title compound, with 4-amino-N, N-diethyl benzene sulfonamide alternate embodiment 183B. 1H NMR(400 MHz, DMSO-d 6) δ 11.16(s, 1H), 9.21(s, 1H), 8.12(d, 2H), 8.01(br s, 1H), 7.85(d, 2H), 7.73(m, 1H), 7.61(m, 3H), 7.11(s, 1H), 3.18(q, 4H), 1.05(t, 6H)。MS(ESI +)m/e 524.2(M + H) +。
Embodiment 295
2-{[2-(cyclopropylamino)-2,3-dihydro-1H-indenes-5-yl] amino }-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 150, prepare title compound (0.07 g), with embodiment 227A, substitute 1,1,2-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-6-amine.With Analogix 280 (SF 12-24 post), carry out chromatographic separation, use 4% ethanol/methylene (containing a small amount of ammonium hydroxide) wash-out 30 minutes. 1H NMR(300 MHz, DMSO-d 6) δ 0.15-0.50(m, 4 H)2.04-2.20(m, 1 H)2.58-2.87(m, 2 H)2.92-3.22(m, 2 H)3.52-3.72(m, 1 H)7.05-7.17(m, 1 H)7.14-7.31(m, 1 H)7.49-7.71(m, 3 H)7.70-7.88(m, 3 H)9.13(s, 1 H)10.63-10.80(m, 1 H)。MS(ESI +)m/z 518.2(M+H) +。
Embodiment 296
6-(2,6-dichlorophenyl)-2-(2-[(2-fluoro ethyl) and amino]-2,3-dihydro-1H-indenes-5-yl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 150, prepare title compound (0.075 g), with embodiment 257A, substitute 1,1,2-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-6-amine.With Analogix 280 (SF 12-24 post), carry out chromatographic separation, use 4% ethanol/methylene (containing a small amount of ammonium hydroxide) wash-out 30 minutes. 1H NMR(300 MHz, DMSO-d 6) δ 2.67(d, 2 H)2.87(d, 2 H)3.09(d, 2 H)3.58(d, 1 H)4.44(d, 2 H)7.11(d, J=1.59 Hz, 1 H)7.22(d, J=7.93 Hz, 1 H)7.52-7.70(m, 3 H)7.69-7.86(m, 3 H)9.14(s, 1 H)10.77(s, 1 H)。MS(ESI +)m/z 524.2(M+H) +。
Embodiment 297
6-(2,6-dichlorophenyl)-2-{[2-(propyl group is amino)-2,3-dihydro-1H-indenes-5-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 150, prepare title compound (0.075 g), with embodiment 258A, substitute 1,1,2-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-6-amine.With Analogix 280 (SF 12-24 post), carry out chromatographic separation, use 4% ethanol/methylene (containing a small amount of ammonium hydroxide) wash-out 30 minutes. 1H NMR(300 MHz, DMSO-d 6) δ 0.73-1.01(m, 3 H)1.29-1.56(m, 2 H)2.52-2.62(m, 2 H)2.58-2.79(m, 2 H)2.87-3.21(m, 2 H)3.42-3.63(m, 1 H)6.97-7.29(m, 2 H)7.37-7.85(m, 7 H)9.14(s, 1 H)10.48-10.94(m, 1 H)。MS(ESI +)m/z 520.2(M+H) +。
Embodiment 298
2-{[4-(2-ethanoyl-2,7-diaza spiro [3.5] ninth of the ten Heavenly Stems-7-yl) phenyl] amino }-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 207, prepare title compound (0.05g), with embodiment 288D alternate embodiment 109B.Crude product is ground together with ethyl acetate, title compound is provided. 1H NMR(300 MHz, DMSO-d 6) δ 1.66-1.94(m, 7 H)3.02-3.22(m, 4 H)3.47-3.63(m, 2 H)3.77-3.90(m, 2 H)6.81-7.26(m, 3 H)7.40-8.01(m, 6 H)9.10(s, 1 H)10.70(s, 1 H)。MS(ESI +)m/z 589.3(M+H) +。
Embodiment 299
6-(2,6-dichlorophenyl)-2-(4-[2-(methylsulfonyl)-2,7-diaza spiro [3.5] ninth of the ten Heavenly Stems-7-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 206, prepare title compound (0.025g), with embodiment 288D alternate embodiment 109B.Crude product is ground together with ethyl acetate, title compound is provided. 1H NMR(300 MHz, DMSO-d 6) δ 1.67-1.94(m, 4 H)2.95-3.09(m, 3 H)3.07-3.18(m, 4 H)3.58-3.74(m, 4 H)6.74-7.27(m, 3 H)7.37-8.01(m, 6 H)9.10(s, 1 H)10.73(s, 1 H)。MS(ESI +)m/z 625.2(M+H) +。
Embodiment 300
7'-{[6-(the chloro-6-fluorophenyl of 2-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino }-N-methyl isophthalic acid ' H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-2'(3'H)-methane amide
By embodiment 228 (0.075 g, 0.134 mmol), methyl carbamic acid 2,5-dioxo pyrrolidin-1-yl ester (0.035 g, 0.201 mmol) and triethylamine (0.093 mL, 0.669 mmol) DMF (2.5 mL) solution at room temperature stirs and spends the night.Water is joined in this reaction mixture at leisure.Solid filtering by obtaining, washes with water, with HPLC, purifies (referring to the scheme of embodiment 241), and the trifluoroacetate of title compound is provided. 1H NMR(400 MHz, CD 3OD)δ 1.07-0.95(m, 4H), 2.77(s, 3H), 3.46(s, 2H), 4.71(s, 2H), 6.93-6.85(m, 1H), 7.08(d, J=1.9 Hz, 1H), 7.38(td, J=8.7, 1.3 Hz, 1H), 7.70-7.47(m, 4H), 7.86(s, 1H), 9.14(s, 1H)。MS(ESI +)m/z 545.2(M+H) +。
Embodiment 301
7'-{[6-(the chloro-6-fluorophenyl of 2-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino }-N-(third-2-yl)-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-2'(3'H)-methane amide
As described in embodiment 300, prepare title compound, with n-Isopropyl isocyanate (2-isocyanatopropane), substitute methyl carbamic acid 2,5-dioxo pyrrolidin-1-yl ester. 1H NMR(400 MHz, CD 3OD)δ 1.01(s, 4H), 1.17(d, J=6.6 Hz, 6H), 3.48(s, 2H), 3.99-3.91(m, 1H), 4.71(s, 2H), 6.92-6.84(m, 1H), 7.07(d, J=1.9 Hz, 1H), 7.42-7.34(m, 1H), 7.67-7.46(m, 4H), 7.84(bs, 1H), 9.13(s, 1H)。MS(ESI +)m/z 573.2(M+H) +。
Embodiment 302
6-(2,6-dichlorophenyl)-2-{[2-(2-fluoro ethyl)-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 150, prepare title compound (0.015 g), with embodiment 281A, substitute 1,1,2-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-6-amine.With Analogix 280 (SF 12-24 post), carry out chromatographic separation, use 40% to 100% ethyl acetate/hexane gradient elution 30 minutes, title compound is provided. 1H NMR(300 MHz, DMSO-d 6) δ 1.25(d, 6 H)2.79(d, 2 H)3.67(d, 2 H)4.59(d, 2 H)7.12(d, J=1.70 Hz, 1 H)7.27-7.55(m, 2 H)7.53-7.87(m, 5 H)9.14(s, 1 H)10.75(s, 1 H)。MS(ESI +)m/z 552.2(M+H) +。
Embodiment 303
6-(2,6-dichlorophenyl)-2-(4-[6-(methylsulfonyl)-2,6-diaza spiro [3.3] heptan-2-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 206, prepare title compound (0.07g), with embodiment 304D alternate embodiment 109B.Crude product is ground together with methylene dichloride, title compound is provided. 1H NMR(300 MHz, DMSO-d 6) δ 2.99(d, 3 H)3.96(d, 4 H)4.09(d, 4 H)6.53(d, J=8.14 Hz, 2 H)7.09(d, J=1.70 Hz, 1 H)7.42-7.98(m, 6 H)9.08(s, 1 H)10.66(s, 1 H)。MS(ESI +)m/z 597.2(M+H) +。
Embodiment 304
2-{[4-(2,6-diaza spiro [3.3] heptan-2-yl) phenyl] amino }-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 304A
6-(4-nitrophenyl)-2,6-diaza spiroheptane-2-formic acid tertiary butyl ester
As described in embodiment 288A, prepare title compound (0.4 g), with 2,6-diaza spiroheptane-2-formic acid tertiary butyl ester list oxalate, substitute 2,7-diaza spiro [3.5] nonane-2-formic acid tertiary butyl ester.MS(ESI +)m/z 320.1(M+H) +。
Embodiment 304B
6-(4-aminophenyl)-2,6-diaza spiroheptane-2-formic acid tertiary butyl ester
As described in embodiment 288B, prepare title compound (0.35 g), with embodiment 304A alternate embodiment 288A.MS(ESI +)m/z 290.1(M+H) +。
Embodiment 304C
6-(4-{[6-(2,6-dichlorophenyl)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } phenyl)-2,6-diaza spiroheptane-2-formic acid tertiary butyl ester
As described in embodiment 109A, prepare title compound (0.08 g), the alternative 7'-amino-1'H-spiral shell of use embodiment 304B [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-2'(3'H)-formic acid tertiary butyl ester.With Analogix 280 (SF 12-24 post), carry out chromatographic separation, use 10% to 70% ethyl acetate/hexane gradient elution 30 minutes.MS(ESI +)m/z 619.3(M+H) +。
Embodiment 304D
2-{[4-(2,6-diaza spiro [3.3] heptan-2-yl) phenyl] amino }-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 109B, prepare title compound (0.07 g), with embodiment 304C alternate embodiment 109A, but dilute this reaction mixture by 100 mL ethyl acetate, use saturated NaHCO 3the aqueous solution, water and salt water washing organism, use MgSO 4dry, filter, concentrated, title compound is provided. 1H NMR(300 MHz, DMSO-d 6) δ 3.85-4.04(m, 4 H)4.04-4.24(m, 4 H)6.54(d, J=8.33 Hz, 2 H)7.10(d, J=1.98 Hz, 1 H)7.38-7.92(m, 7 H)9.08(s, 1 H)10.67(s, 1 H)。MS(ESI +)m/z 519.2(M+H) +。
Embodiment 305
6-(2,6-dichlorophenyl)-2-{[2-(pyrrolidin-1-yl)-2,3-dihydro-1H-indenes-5-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 150, prepare title compound (0.085 g), with embodiment 259A, substitute 1,1,2-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-6-amine.With Analogix 280 (SF 12-24 post), carry out chromatographic separation, use 4% ethanol/methylene (containing a small amount of ammonium hydroxide) wash-out 30 minutes.This compound is dissolved in methyl alcohol, with excessive 2M HCl/ diethyl ether, processes, stir, until start to form solid.With ether, dilute this mixture, stir 10 minutes, filter, title compound is provided. 1H NMR(500 MHz, DMSO-d 6) δ 1.99(d, 4 H)3.10(d, 2 H)3.33(d, 5 H)4.10(d, 1 H)7.13(d, J=1.53 Hz, 1 H)7.31(s, 1 H)7.45-8.04(m, 6 H)9.16(s, 1 H)10.89(s, 1 H)11.50(s, 1 H)。MS(ESI +)m/z 532.2(M+H) +。
Embodiment 306
6-(2,6-dichlorophenyl)-2-(2-[(3S) and-3-fluoropyrrolidine-1-yl]-2,3-dihydro-1H-indenes-5-yl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 150, prepare title compound (0.085 g), with embodiment 256A, substitute 1,1,2-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-6-amine.With Analogix 280 (SF 12-24 post), carry out chromatographic separation, use 4% ethanol/methylene (containing a small amount of ammonium hydroxide) wash-out 30 minutes.This compound is dissolved in methyl alcohol, with excessive 2M HCl/ diethyl ether, processes, stir, until start to form solid.With ether, dilute this mixture, stir 10 minutes, filter, title compound is provided. 1H NMR(500 MHz, DMSO-d 6) δ 1.99-2.44(m, 2 H)3.19-3.64(m, 6 H)3.63-3.80(m, 2 H)4.05-4.35(m, 1 H)5.34-5.69(m, 1 H)7.13(s, 1 H)7.31(s, 1 H)7.51-7.99(m, 6 H)9.16(s, 1 H)10.89(s, 1 H)。MS(ESI +)m/z 550.2(M+H) +。
Embodiment 307
6-(2,6-dichlorophenyl)-2-[(4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 307A
7-{[6-(2,6-dichlorophenyl)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino }-4,4-dimethyl-3,4-dihydro-isoquinoline-2 (1H)-formic acid tertiary butyl ester
As described in embodiment 109A, prepare title compound (0.42 g), with 7-amino-4,4-dimethyl-3,4-dihydro-isoquinoline-2 (1H)-formic acid tertiary butyl ester substitutes 7'-amino-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-2'(3'H)-formic acid tertiary butyl ester.From crude product reaction mixture, grind together with dichloromethane/ethyl acetate, obtain final compound.MS(ESI +)m/z 606.01(M+H) +。
Embodiment 307B
6-(2,6-dichlorophenyl)-2-[(4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 109B, prepare title compound (0.4g), with embodiment 307A alternate embodiment 109A.Tfa salt is dissolved in methyl alcohol, with excessive 2M HCl/ diethyl ether, processes, stir, until start to form solid.With ether, dilute this mixture, stir 10 minutes, filter, title compound is provided. 1H NMR(500 MHz, DMSO-d 6) δ 1.37(d, 6 H)3.22(d, 2 H)4.28(d, 2 H)7.14(d, J=1.53 Hz, 1 H)7.42-8.02(m, 7 H)9.17(s, 1 H)9.48-9.70(m, 2 H)10.93(s, 1 H)。MS(ESI +)m/z 506.2(M+H) +。
Embodiment 308
6-(2,6-dichlorophenyl)-2-{[4-(piperidin-4-yl is amino) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 308A
4-[(4-{[6-(2,6-dichlorophenyl)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } phenyl) amino] piperidines-1-formic acid tertiary butyl ester
As described in embodiment 109A, prepare title compound (0.15 g), the alternative 7'-amino-1'H-spiral shell of use 4-(4-aminophenyl is amino)-piperidines-1-formic acid tertiary butyl ester [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-2'(3'H)-formic acid tertiary butyl ester.From crude product reaction mixture, grind together with dichloromethane/ethyl acetate, obtain final compound.MS(ESI +)m/z 620.95(M+H) +。
Embodiment 308B
6-(2,6-dichlorophenyl)-2-{[4-(piperidin-4-yl is amino) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 109B, prepare title compound (0.14g), with embodiment 308A alternate embodiment 109A.Tfa salt is dissolved in methyl alcohol, with excessive 2M HCl/ diethyl ether, processes, stir, until start to form solid.With ether, dilute this mixture, stir 10 minutes, filter, title compound is provided. 1H NMR(300 MHz, DMSO-d 6) δ 1.46-1.75(m, 2 H)1.96-2.17(m, 2 H)2.84-3.14(m, 2 H)3.21-3.38(m, 2 H)6.92(s, 2 H)7.11(d, J=1.59 Hz, 1 H)7.41-7.91(m, 6 H)8.69(d, J=38.48 Hz, 2 H)9.10(s, 1 H)10.71(s, 1 H)。MS(ESI +)m/z 521.3(M+H) +。
Embodiment 309
6-(the chloro-6-fluorophenyl of 2-)-2-{[4-(1-methyl piperidine-4-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 123B, prepare title compound, with embodiment 95C and 4-(1-methyl piperidine-4-yl) aniline difference alternate embodiment 123A and 4-(4-methylpiperazine-1-yl) aniline.Carry out aqueous solution processing, then carry out HPLC purifying. 1H NMR(400 MHz, CD 3OD)δ 2.12-1.89(m, 2H), 2.21-2.12(m, 2H), 2.97-2.86(m, 4H), 3.23-3.09(m, 2H), 3.67-3.60(m, 2H), 7.08(d, J=1.9 Hz, 1H), 7.46-7.22(m, 3H), 7.65-7.52(m, 2H), 7.90-7.71(m, 3H), 9.14(bs, 1H)。MS(ESI +)m/z 504.3(M+H) +。
Embodiment 310
2-[(2-ethanoyl-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl) amino]-6-(the chloro-6-fluorophenyl of 2-) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 310A
6-(the chloro-6-fluorophenyl of 2-)-2-[(4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 160A and embodiment 160B, prepare title compound, in embodiment 160A, with embodiment 95C and 7-amino-4,4-dimethyl-3,4-dihydro-isoquinoline-2 (1H)-formic acid tertiary butyl ester difference alternate embodiment 123A and 7'-amino-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-2'(3'H)-formic acid tertiary butyl ester.
Embodiment 310B
2-[(2-ethanoyl-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl) amino]-6-(the chloro-6-fluorophenyl of 2-) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 241, prepare title compound, by embodiment 310A alternate embodiment 228. 1H NMR(400 MHz, CD 3OD)δ 1.29(s, 3H), 1.34(s, 3H), 2.26-2.19(m, 3H), 3.63-3.54(m, 2H), 4.80-4.78(m, 2H), 7.07(s, 1H), 7.49-7.33(m, 2H), 7.55-7.49(m, 1H), 7.71-7.54(m, 3H), 7.85(bs, 1H), 9.14(s, 1H)。MS(ESI +)m/z 532.3(M+H) +。
Embodiment 311
6-(the chloro-6-fluorophenyl of 2-)-2-{[2-(cyclopropyl carbonyl)-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 241, prepare title compound, with embodiment 310A and cyclopropane-carboxylic acid difference alternate embodiment 228 and acetic acid. 1H NMR(400 MHz, DMSO-d 6)δ 0.85-0.70(m, 4H), 1.32-1.18(m, 6H), 2.20-2.05(m, 1H), 3.54(s, 0.7H), 3.74(s, 1.3H), 4.71(s, 1.3H), 4.99(s, 0.7H), 7.12(d, J=1.8 Hz, 1H), 7.91-7.15(m, 7H), 9.15(s, 1H), 10.80(bs, 1H)。MS(ESI +)m/z 558.3(M+H) +。
Embodiment 312
6-(the chloro-6-fluorophenyl of 2-)-2-{[4,4-dimethyl-2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 172, prepare title compound, with embodiment 310A alternate embodiment 160B. 1H NMR(400 MHz, DMSO-d 6)δ 1.30(s, 6H), 3.01(s, 3H), 3.17(s, 2H), 4.39(s, 2H), 7.13(d, J=1.8 Hz, 1H), 7.88-7.22(m, 7H), 9.15(s, 1H), 10.83(bs, 1H)。MS(ESI +)m/z 568.2(M+H) +。
Embodiment 313
2-{[4-(2,6-diaza spiro [3.4] pungent-2-yl) phenyl] amino }-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 313A
2-(4-nitrophenyl)-2,6-diaza spiro [3.4] octane-6-formic acid tertiary butyl ester
As described in embodiment 288A, prepare title compound (0.48 g), by 2,6-diaza spiro [3.4] octane-6-formic acid tertiary butyl ester, substitute 2,7-diaza spiro [3.5] nonane-2-formic acid tertiary butyl ester.MS(ESI +)m/z 334.1(M+H) +。
Embodiment 313B
2-(4-aminophenyl)-2,6-diaza spiro [3.4] octane-6-formic acid tertiary butyl ester
As described in embodiment 288B, prepare title compound (0.4 g), with embodiment 313A alternate embodiment 288A.MS(ESI +)m/z 304.1(M+H) +。
Embodiment 313C
2-(4-{[6-(2,6-dichlorophenyl)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } phenyl)-2,6-diaza spiro [3.4] octane-6-formic acid tertiary butyl ester
As described in embodiment 109A, prepare title compound (0.12 g), the alternative 7'-amino-1'H-spiral shell of use embodiment 313B [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-2'(3'H)-formic acid tertiary butyl ester.With Analogix 280 (SF 25-40 post), carry out chromatographic separation, use 40% to 100% ethyl acetate/hexane gradient elution 30 minutes, title compound is provided.MS(ESI +)m/z 635.4(M+H) +。
Embodiment 313D
2-{[4-(2,6-diaza spiro [3.4] pungent-2-yl) phenyl] amino }-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 109B, prepare title compound (0.1g), with embodiment 313C alternate embodiment 109A, and this reaction mixture is diluted by 100 mL ethyl acetate.Use saturated NaHCO 3the aqueous solution, water and salt water washing organism, use MgSO 4dry, filter, concentrate, the free alkali of title compound is provided. 1H NMR(300 MHz, DMSO-d 6) δ 2.18(d, 2 H)3.16(d, 4 H)3.79(d, 4 H)6.54(d, J=8.14 Hz, 2 H)7.10(d, J=1.70 Hz, 1 H)7.38-7.92(m, 7 H)8.98-9.16(m, 1 H)10.66(s, 1 H)。MS(ESI +)m/z 533.3(M+H) +。
Embodiment 314
2-{[4-(2,7-diaza spiro [3.5] ninth of the ten Heavenly Stems-2-yl) phenyl] amino }-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 314A
2-(4-nitrophenyl)-2,7-diaza spiro [3.5] nonane-7-formic acid tertiary butyl ester
As described in embodiment 288A, prepare title compound (0.5 g), by 2,7-diaza spiro [3.5] nonane-7-formic acid tertiary butyl ester, substitute 2,7-diaza spiro [3.5] nonane-2-formic acid tertiary butyl ester.MS(ESI +)m/z 348.1(M+H) +。
Embodiment 314B
2-(4-aminophenyl)-2,7-diaza spiro [3.5] nonane-7-formic acid tertiary butyl ester
As described in embodiment 288B, prepare title compound (0.4 g), with embodiment 314A alternate embodiment 288A.MS(ESI +)m/z 317.9(M+H) +。
Embodiment 314C
2-(4-{[6-(2,6-dichlorophenyl)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } phenyl)-2,7-diaza spiro [3.5] nonane-7-formic acid tertiary butyl ester
As described in embodiment 109A, prepare title compound (0.12 g), the alternative 7'-amino-1'H-spiral shell of use embodiment 314B [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-2'(3'H)-formic acid tertiary butyl ester.With Analogix 280 (SF 12-24 post), carry out chromatographic separation, use 40% to 100% ethyl acetate/hexane gradient elution 30 minutes.MS(ESI +)m/z 647.26(M+H) +。
Embodiment 314D
2-{[4-(2,7-diaza spiro [3.5] ninth of the ten Heavenly Stems-2-yl) phenyl] amino }-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 109B, prepare title compound (0.12g), with embodiment 314C alternate embodiment 109A, but dilute this reaction mixture by ethyl acetate, and by the saturated NaHCO of organism 3solution washing.The emulsion obtaining is filtered, and retain solid.With salt water washing organism, use MgSO 4dry, filter, concentrated.The solid that filtration step is obtained joins wherein, and by this material high vacuum dry, provides title compound. 1H NMR(300 MHz, DMSO-d 6) δ 1.93(d, 4 H)3.02(d, 4 H)3.61(d, 4 H)6.51(d, J=8.48 Hz, 2 H)7.09(d, J=2.03 Hz, 1 H)7.36-8.01(m, 6 H)8.48(s, 2 H)9.08(s, 1 H)10.65(s, 1 H)。MS(ESI +)m/z 547.3(M+H) +。
Embodiment 315
6-(2,6-dichlorophenyl)-2-(4-[(3S) and-3-(dimethylamino) pyrrolidin-1-yl] phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 150, prepare title compound (0.08 g), with (S)-1-(4-aminophenyl)-N, N-dimethyl pyrrolidine-3-amine substitutes 1,1,2-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-6-amine.With Analogix 280 (SF 12-24 post), carry out chromatographic separation, use 4% ethanol/methylene (containing a small amount of ammonium hydroxide) wash-out 30 minutes.The compound of purifying is dissolved in methyl alcohol, with excessive 2M HCl/ diethyl ether, processes, stir, until start to form solid.With ether, dilute this mixture, stir 10 minutes, filter, title compound is provided. 1H NMR(300 MHz, DMSO-d 6) δ 2.30(d, 2 H)2.82(d, 6 H)3.26(d, 1 H)3.65(d, 2 H)3.99(d, 1 H)6.72(d, J=8.33 Hz, 2 H)7.10(d, J=1.59 Hz, 1 H)7.43-7.91(m, 6 H)9.08(s, 1 H)10.52-10.80(m, 2 H)。MS(ESI +)m/z 535.3(M+H) +。
Embodiment 316
6-(the chloro-6-fluorophenyl of 2-)-2-{[2-(hydroxyacetyl)-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 241, prepare title compound, with embodiment 310A and 2-oxyacetic acid difference alternate embodiment 228 and acetic acid.
Embodiment 317
7-{[6-(the chloro-6-fluorophenyl of 2-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino }-4,4-dimethyl-3,4-dihydro-isoquinoline-2 (1H)-sulphonamide
CH to embodiment 310A (0.070 g, 0.124 mmol) 2cl 2in (6 mL) suspension, add triethylamine (0.069 mL; 0.497 mmol) and (tertbutyloxycarbonyl) { [4-(dimethyl imido grpup (iminio)) pyridine-[(4H)-yl] alkylsulfonyl } amides (azanide) (US2007/0149512; 0.037 g, 0.124 mmol).This reaction mixture is stirred and spent the night, and process with trifluoroacetic acid (0.5 mL, 6.49 mmol).After 4 hours, concentrated this reaction mixture, purifies (referring to the scheme of embodiment 1F) with HPLC, and the trifluoroacetate of title compound is provided.
Embodiment 318
2-[(2-ethanoyl-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl) amino]-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 207, prepare title compound (0.075g), with embodiment 307B alternate embodiment 109B.With Analogix 280 (SF 25-40 post), carry out chromatographic separation, use 0% to 6% ethanol/methylene gradient elution 30 minutes. 1H NMR(300 MHz, DMSO-d 6) δ 1.16-1.36(m, 6 H)2.04-2.22(m, 3 H)3.39-3.59(m, 2 H)4.51-4.92(m, 2 H)7.01-7.20(m, 1 H)7.30-8.06(m, 7 H)9.05-9.32(m, 1 H)10.51-11.00(m, 1 H)。MS(ESI +)m/z 548.3(M+H) +。
Embodiment 319
6-(2,6-dichlorophenyl)-2-{[4,4-dimethyl-2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 206, prepare title compound (0.07g), with embodiment 307B alternate embodiment 109B.With Analogix 280 (SF 12-24 post), carry out chromatographic separation, use 40% to 100% ethyl acetate/hexane gradient elution 30 minutes. 1H NMR(300 MHz, DMSO-d 6) δ 1.30(d, 6 H)3.00(d, 3 H)3.16(d, 2 H)4.38(d, 2 H)7.13(d, J=1.70 Hz, 1 H)7.35-7.95(m, 7 H)9.16(s, 1 H)10.82(s, 1 H)。MS(ESI +)m/z 584.2(M+H) +。
Embodiment 320
6-(2,6-dichlorophenyl)-2-{[2-(ethylsulfonyl)-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 206, prepare title compound (0.07g), with embodiment 307B alternate embodiment 109B, ethyl sulfonyl chloride substitutes methylsulfonyl chloride.With Analogix 280 (SF 12-24 post), carry out chromatographic separation, use 40% to 70% ethyl acetate/hexane gradient elution 30 minutes. 1H NMR(300 MHz, DMSO-d 6) δ 1.12-1.46(m, 9 H)3.16(d, 4 H)4.44(d, 2 H)7.13(d, J=1.70 Hz, 1 H)7.28-8.05(m, 7 H)9.16(s, 1 H)10.82(s, 1 H)。MS(ESI +)m/z 598.2(M+H) +。
Embodiment 321
2-(4-[(1-ethanoyl piperidin-4-yl) and amino] phenyl } amino)-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 207, prepare title compound (0.025g), with embodiment 308B alternate embodiment 109B.With Analogix 280 (SF 25-40 post), carry out chromatographic separation, use 0% to 6% ethanol/methylene gradient elution 30 minutes. 1H NMR(300 MHz, DMSO-d 6) δ 1.27(d, 2 H)1.95(d, 4 H)2.78(d, 1 H)3.16(d, 1 H)3.49(d, 1 H)3.81(d, 1 H)4.23(d, 1 H)5.52(d, J=8.14 Hz, 1 H)6.68(d, J=8.82 Hz, 2 H)7.09(d, J=1.70 Hz, 1 H)7.39(s, 1 H)7.48-7.68(m, 3 H)7.71-7.82(m, 3 H)9.05(s, 1 H)10.56(s, 1 H)。MS(ESI +)m/z 563.4(M+H) +。
Embodiment 322
6-(2,6-dichlorophenyl)-2-[(4-{[1-(methylsulfonyl) piperidin-4-yl] amino } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 206, prepare title compound (0.02 g), with embodiment 308B alternate embodiment 109B.With Analogix 280 (SF 12-24 post), carry out chromatographic separation, use 40% to 100% ethyl acetate/hexane gradient elution 30 minutes. 1H NMR(300 MHz, DMSO-d 6) δ 1.30-1.64(m, 2 H)1.74-2.19(m, 2 H)2.81-3.01(m, 5 H)3.35-3.51(m, 1 H)3.44-3.65(m, 2 H)5.56(s, 1 H)6.68(d, J=8.33 Hz, 2 H)7.09(d, J=1.59 Hz, 1 H)7.37(s, 1 H)7.50-7.69(m, 2 H)7.69-7.83(m, 3 H)9.06(s, 1 H)10.58(s, 1 H)。MS(ESI +)m/z 599.2(M+H) +。
Embodiment 323
6-(2,6-dichlorophenyl)-2-{[4-(9-methyl-3,9-diaza spiro [5.5] 10 one-3-yls) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 150, prepare title compound (0.11 g), with 4-(9-methyl-3,9-diaza spiro [5.5] 10 one-3-yls) aniline, substitute 1,1,2-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-6-amine.With Analogix 280 (SF 25-40 post), carry out chromatographic separation, use 4% ethanol/methylene (containing a small amount of ammonium hydroxide) wash-out 30 minutes.Purifying substance is dissolved in methyl alcohol, with excessive 2M HCl/ diethyl ether, processes, stir, until start to form solid.With ether, dilute this mixture, stir 10 minutes, filter, title compound is provided. 1H NMR(300 MHz, DMSO-d 6) δ 1.80(d, 10 H)2.74(d, 3 H)3.06(d, 2 H)3.27(d, 2 H)7.13(d, J=1.59 Hz, 1 H)7.40-8.11(m, 9 H)9.17(s, 1 H)9.93(s, 1 H)10.91(s, 1 H)。MS(ESI +)m/z 589.4(M+H) +。
Embodiment 324
6-(2,6-dichlorophenyl)-2-(4-[6-(methylsulfonyl)-2, and 6-diaza spiro [3.4] is pungent-2-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 206, prepare title compound (0.045 g), with embodiment 313D alternate embodiment 109B.Crude product is ground together with methylene dichloride, title compound is provided. 1H NMR(300 MHz, DMSO-d 6) δ 2.17(d, 2 H)2.94(d, 3 H)3.46(d, 2 H)3.79(d, 4 H)6.54(d, J=8.73 Hz, 2 H)7.09(d, J=1.98 Hz, 1 H)7.36-7.89(m, 6 H)9.08(s, 1 H)10.66(s, 1 H)。MS(ESI +)m/z 611.3(M+H) +。
Embodiment 325
6-(2-chloro-phenyl-)-2-({ 4-[(8aS)-hexahydropyrrolo is [1,2-a] pyrazine-2 (1H)-yl also] phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 325A
(S)-2-(4-nitrophenyl) octahydro pyrrolo-[1,2-a] pyrazine
As described in embodiment 183A, prepare title compound, with (S)-octahydro pyrrolo-[1,2-a] pyrazine, substitute two (2-methoxy ethyl) amine.MS(ESI +)m/e 248.2(M + H) +。
Embodiment 325B
(S)-4-(hexahydropyrrolo is [1,2-a] pyrazine-2 (1H)-yl also) aniline
As described in embodiment 183B, prepare title compound, with embodiment 325A alternate embodiment 183B.MS(ESI +)m/e 218.2(M + H) +。
Embodiment 325C
6-(2-chloro-phenyl-)-2-({ 4-[(8aS)-hexahydropyrrolo is [1,2-a] pyrazine-2 (1H)-yl also] phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 183C, prepare title compound, with embodiment 325B alternate embodiment 183B. 1H NMR(400 MHz, DMSO-d 6, 90o) δ 10.28(s, 1H), 9.05(s, 1H), 7.68(m, 4H), 7.53(m, 3H), 3.51(m, 9H), 2.14(m, 4H)。MS(ESI +)m/e 513.3(M + H) +。
Embodiment 326
6-(2,6-dichlorophenyl)-2-({ 4-[(3aR, 6aR)-5-methyl hexahydropyrrolo is [3,4-b] pyrroles-1 (2H)-yl also] phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 150, prepare title compound (0.025 g), with 4-((3aR, 6aR)-5-methyl hexahydropyrrolo also [3,4-b] pyrroles-1 (2H)-yl) alternative 1,1, the 2-of aniline two HCl salt trimethylammonium-1,2,3,4-tetrahydroisoquinoline-6-amine.With Analogix 280 (SF 12-24 post), carry out chromatographic separation, use 4% ethanol/methylene (containing a small amount of ammonium hydroxide) wash-out 30 minutes.This compound is dissolved in methyl alcohol, with 2M HCl/ diethyl ether, processes 20 minutes, filter, title compound is provided. 1H NMR(300 MHz, DMSO-d 6) δ 1.85-2.36(m, 3 H)2.71-2.90(m, 3 H)3.03-3.21(m, 1 H)3.21-3.40(m, 2 H)3.98-4.48(m, 3 H)6.48-6.87(m, 2 H)7.11(s, 1 H)7.43-7.93(m, 7 H)9.09(d, J=1.59 Hz, 1 H)10.05(s, 1 H)10.71(s, 1 H)。MS(ESI +)m/z 547.3(M+H) +。
Embodiment 327
6-(2,6-dichlorophenyl)-2-[(4-{[2-(dimethylamino) ethyl] (ethyl) amino } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 150, prepare title compound (0.025 g), use N 1-(2-(dimethylamino) ethyl)-N 1-ethylbenzene-Isosorbide-5-Nitrae-diamines substitutes 1,1,2-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-6-amine.Use Analogix280 SF 15-12 column purification crude product (0% to 4% ethanol/methylene gradient elution 30).Solid is dissolved in methyl alcohol, with 2M HCl/ diethyl ether, processes 20 minutes, filter. 1H NMR(300 MHz, DMSO-d 6) δ 1.08(d, 3 H)2.86(d, 6 H)3.20(d, 2 H)3.37(d, 2 H)3.64(d, 2 H)6.89(d, J=8.14 Hz, 2 H)7.11(s, 1 H)7.38-8.03(m, 6 H)9.09(s, 1 H)10.06(s, 1 H)10.43-10.81(m, 1 H)。MS(ESI +)m/z 537.2(M+H) +。
Embodiment 328
6-(2,6-dichlorophenyl)-2-[(4-{ third-2-base [2-(third-2-base is amino) ethyl] amino } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 150, prepare title compound (0.025 g), use N 1-sec.-propyl-N 1-(2-(isopropylamine base) ethyl) benzene-Isosorbide-5-Nitrae-diamines substitutes 1,1,2-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-6-amine.Use Analogix280 SF 15-12 column purification crude product (0% to 4% ethanol/methylene gradient elution 30).The compound of purifying is dissolved in methyl alcohol, with 2M HCl/ diethyl ether, processes 20 minutes, filter, title compound is provided. 1H NMR(300 MHz, DMSO-d 6) δ 1.12-1.42(m, 12 H)3.11-3.31(m, 2 H)3.39-3.57(m, 4 H)6.72(s, 2 H)7.10(d, J=1.98 Hz, 1 H)7.48(s, 1 H)7.55-7.72(m, 3 H)7.70-7.85(m, 3 H)9.08(s, 1 H)10.65(s, 1 H)。MS(ESI +)m/z 565.3(M+H) +。
Embodiment 329
2-[(2-ethanoyl-1,2,3,4-tetrahydroisoquinoline-7-yl) amino]-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 207, prepare title compound (0.085g), with embodiment 111B alternate embodiment 109B.With Analogix 280 (SF 25-40 post), carry out chromatographic separation, use 0% to 7% ethanol/methylene gradient elution 30 minutes. 1H NMR(300 MHz, DMSO-d 6) δ 2.04-2.16(m, 3 H)2.66-2.96(m, 2 H)3.55-3.78(m, 2 H)4.51-4.79(m, 2 H)7.12(s, 1 H)7.23(d, J=8.33 Hz, 1 H)7.52-7.92(m, 6 H)9.16(s, 1 H)10.82(s, 1 H)。MS(ESI +)m/z 520.3(M+H) +。
Embodiment 330
6-(2,6-dichlorophenyl)-2-{[2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 206, prepare title compound (0.09 g), with embodiment 122 alternate embodiment 109B.Crude product is ground together with ethyl acetate, title compound is provided. 1H NMR(300 MHz, DMSO-d 6) δ 2.86-3.08(m, 5 H)3.46(t, J=5.95 Hz, 2 H)4.37(s, 2 H)7.12(d, J=1.98 Hz, 1 H)7.24(d, J=8.73 Hz, 1 H)7.54-7.91(m, 6 H)9.17(s, 1 H)10.84(s, 1 H)。MS(ESI +)m/z 556.2(M+H) +。
Embodiment 331
2-[(2-ethanoyl-1,2,3,4-tetrahydroisoquinoline-6-yl) amino]-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
As described in embodiment 207, prepare title compound (0.085g), with embodiment 122 alternate embodiment 109B.Treated solid matter is filtered, title compound is provided. 1H NMR(300 MHz, DMSO-d 6) δ 2.10(s, 3 H)2.65-3.04(m, 2 H)3.68(t, J=5.93 Hz, 2 H)4.61(d, J=15.60 Hz, 2 H)7.10(d, J=1.70 Hz, 1 H)7.22(d, J=8.14 Hz, 1 H)7.51-7.70(m, 3 H)7.71-7.84(m, 3 H)9.12(s, 1 H)10.81(s, 1 H)。MS(ESI +)m/z 520.3(M+H) +。
Embodiment 332
6-(2-chloro-phenyl-)-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-thioketones
Embodiment 332A
4-(the chloro-phenyl of 2-)-8-methyl sulfenyl-4H-3,4,7,9,9b-pentaaza-cyclopenta [a] naphthalene-5-thioketones
Toluene (40 mL) solution of embodiment 1D (0.730 g, 2.123 mmol) and Lloyd's's reagent (Lawesson's) (0.515 g, 1.274 mmol) is heated to reflux, keeps 4 hours.Concentrated this reaction mixture, purifying on 40 g posts, is used ISCO Companion flash chromatographic system, with hexane/ethyl acetate (1:1 to 4:6) wash-out, provides title compound.
Embodiment 332B
6-(2-chloro-phenyl-)-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-thioketones
In Biotage microwave reactor, by embodiment 332A (100.0 mg, 0.278 mmol), 4-(4-methylpiperazine-1-yl) aniline (106 mg, 0.556 mmol) and 1 DMF mixture in acetonitrile (4 mL) at 180 ℃, heat 180 minutes.Concentrated this reaction mixture, purifies (referring to the scheme of embodiment 1F) with HPLC, and the trifluoroacetate of title compound is provided. 1H NMR(400 MHz, CD 3OD)δ 2.99(s, 3H), 3.19-3.00(m, 2H), 3.35-3.27(m, 2H), 3.67-3.59(m, 2H), 3.90-3.81(m, 2H), 7.14-7.04(m, 3H), 7.60-7.45(m, 3H), 7.79-7.62(m, 3H), 7.98-7.83(m, 1H), 9.51(s, 1H)。MS(ESI +)m/z 503.1(M+H) +。
Embodiment 333
6-(2-chloro-phenyl-)-5-imino--N-[4-(4-methylpiperazine-1-yl) phenyl]-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-amine also
In 25 mL stainless steel reactors, by 7M NH 3/ methyl alcohol (10 mL) joins in embodiment 332B (4.98 mg, 6.81 μ mol).This mixture is stirred 1 hour at 120 ℃.Concentrated this reaction mixture, purifies (referring to the scheme of embodiment 1F) with HPLC, and the trifluoroacetate of title compound is provided. 1H NMR(400 MHz, CD 3OD)δ 2.99(s, 3H), 3.13-3.03(m, 2H), 3.38-3.24(m, 2H), 3.72-3.56(m, 2H), 3.95-3.80(m, 2H), 7.22-7.07(m, 3H), 7.80-7.64(m, 5H), 7.86-7.83(m, 1H), 8.05-7.98(m, 1H), 9.46-9.43(m, 1H)。MS(ESI +)m/z 486.3(M+H) +。
Embodiment 334
6-(2-chloro-phenyl-)-2-[(2,4,4-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-7-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-thioketones
By embodiment 332A (126 mg, 0.35 mmol) and 2,4,4-trimethylammonium-1, the mixture of 2,3,4-tetrahydroisoquinoline-7-amine (133 mg, 0.70 mmol) heats 4.5 hours purely at 140 ℃.By ethyl acetate, process this reaction mixture, and use saturated NaHCO 3washing.By organic layer MgSO 4dry, filter, concentrated, purifying on 12 g posts, is used ISCO Companion flash chromatographic system, with methanol/ethyl acetate (5:95 to 10:90) wash-out, then carry out HPLC (referring to the scheme of embodiment 1F), the trifluoroacetate of title compound is provided. 1H NMR(400 MHz, CD 3OD)δ 1.49(s, 6H), 3.12(s, 3H), 3.40-3.23(m, 1H), 3.63-3.48(m, 1H), 4.62-4.41(m, 2H), 7.13(d, J=1.8 Hz, 1H), 7.61-7.46(m, 4H), 7.70-7.64(m, 1H), 7.83-7.72(m, 2H), 7.93(d, J=1.8 Hz, 1H), 9.59(s, 1H)。MS(ESI +)m/z 502.1(M+H) +。
Embodiment 335
6-(2-chloro-phenyl-)-5-imino--N-(2,4,4-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-7-yl)-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-amine also
In 25 mL stainless steel reactors, by 7M NH 3/ methyl alcohol (12 mL) joins in embodiment 334 (10.5 mg).At 75 ℃, stir this mixture 8 hours.Concentrated this reaction mixture, purifies (referring to the scheme of embodiment 1F) with HPLC, and the trifluoroacetate of title compound is provided. 1H NMR(400 MHz, CD 3OD)δ 1.43(s, 6H), 3.13(s, 3H), 3.64-3.27(m, 2H), 4.68-4.40(m, 2H), 7.22(bs, 1H), 7.82-7.57(m, 5H), 7.87-7.84(m, 2H), 8.06(s, 1H), 9.55-9.48(m, 1H)。MS(ESI +)m/z 485.2(M+H) +。
Use the method similar with embodiment 1-335 institute described method, prepare following compounds.
Embodiment 336
6-(3-fluorophenyl)-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 337
6-(3-chloro-phenyl-)-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 338
6-(2,4-Dimethoxyphenyl)-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 339
6-(2-chloro-phenyl-)-2-{[5-(4-ethyl piperazidine-1-yl) pyridine-2-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 340
The chloro-4-of 6-[2-(trifluoromethyl) phenyl]-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 341
2-{[4-(4-methylpiperazine-1-yl) phenyl] amino }-6-[2-(trifluoromethoxy) phenyl] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 342
4-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } phenylformic acid
Embodiment 343
2-[(4-bromophenyl) amino]-6-(2-chloro-phenyl-) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 344
6-(3-methoxyl group-2-aminomethyl phenyl)-2-(phenyl amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 345
2-{[4-(Isosorbide-5-Nitrae-Diazesuberane-1-yl)-3-aminomethyl phenyl] amino }-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 346
2-{[4-(4-methylpiperazine-1-yl) phenyl] amino }-6-(third-2-yl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 347
6-(2-chloro-phenyl-)-2-{[3, the fluoro-4-of 5-bis-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 348
6-(2-chloro-phenyl-)-2-{[4-(trifluoromethyl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 349
6-(2-chloro-phenyl-)-2-{[4-(1,3-thiazoles-4-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 350
6-(2-chloro-phenyl-)-2-{[4-(1,3-thiazoles-2-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 351
6-(2-chloro-phenyl-)-2-{[4-(1,8-naphthyridines-2-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 352
6-(2-chloro-phenyl-)-2-(4-[(2S) and-2-(trifluoromethyl) pyrrolidin-1-yl] phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 353
The chloro-4-of 2-{[3-(4-methylpiperazine-1-yl)-5-(trifluoromethyl) phenyl] amino }-6-(2-chloro-phenyl-) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 354
The chloro-4-of 6-(2-chloro-phenyl-)-2-{[3-(piperazine-1-yl)-5-(trifluoromethyl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 355
6-(2-chloro-phenyl-)-2-[(2'-methyl-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-thioketones
Embodiment 356
2-{[7-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino }-4,4-dimethyl-3,4-dihydro-isoquinoline-2 (1H)-yl] methyl } benzonitrile
Embodiment 357
6-(2-chloro-phenyl-)-2-{[4,4-dimethyl-2-(4-propoxy-benzyl)-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 358
6-(2-chloro-phenyl-)-2-(the fluoro-5-of 2-[3-(trifluoromethyl) benzyl] and-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 359
6-(2-chloro-phenyl-)-2-[(4-{2-[(2R)-2-methylpyrrolidin-1-yl] ethyl } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 360
6-(2-chloro-phenyl-)-2-(4-[2-(morpholine-4-yl)-1,3-thiazoles-4-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 361
6-(2-chloro-phenyl-)-2-(4-[2-(6-toluquinoline-2-yl) ethyl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one
Embodiment 362
Wee1 test:
In conjunction with test, (it monitors competitive Wee 1 inhibitor to the competitive kinases probe of the ATP-of quick reversibility Oregon Green-mark (N-(2-(2-(2-(4-(4-(the chloro-4-of 5-(2-(1-hydroxyl cyclobutyl) thiazole-5-yl)-1H-pyrrolo-[2 to the fluorescence balance of differentiating duration of service, 3-b] pyridine-2-yl) phenyl) piperazine-1-yl) oxyethyl group) oxyethyl group) ethyl)-2', the fluoro-3' of 7'-bis-, 6'-dihydroxyl-3-oxo-3H-spiral shell [isobenzofuran-1,9'-xanthene]-5-methane amide) displacement), check Wee 1 kinases.By the Wee of GST mark 1 kinases (Carnabio #05-177,2 nM final concns) and fluorescent probe (final concn 300 nM, K d=137 nM) and the anti-GST antibody of terbium mark (final concn 1 nM, Invitrogen #PV3551) mix, then mix with inhibitor (0.003 to 10 micromole), at final volume 18 μ l kinase buffer liquid (20 mM HEPES, pH7.5,10 mM MgCl 2, 100 μ M Na 3vO 4, 0.0075% Triton X-100,1 mM DTT, 2% DMSO) in, cultivate (1 hour), reach balance, and use Envision plate reader (Perkin Elmer; Ex=337 nM, em=495/520 nM) minute resolution fluorescence.
The enzyme that table 1 has been described model compounds suppresses data (K i).In table 1, " A " represents K ibe less than 10 nM, " B " represents K ibetween 10 nM and 100 nM, " C " represents K ibe greater than 100 nM.
Embodiment Wee-1 suppresses Embodiment Wee-1 suppresses
1 A 182 A
2 B 183 B
3 C 184 A
4 A 185 A
5 B 186 A
6 A 187 A
7 B 188 A
8 A 189 B
9 A 190 A
10 A 191 A
11 B 192 B
12 A 193 A
13 A 194 A
14 A 195 A
15 B 196 A
16 B 197 A
17 C 198 A
18 B 199 A
19 B 200 A
20 B 201 A
21 A 202 A
22 A 203 A
23 C 204 A
24 C 205 A
25 A 206 A
26 B 207 A
27 B 208 A
28 B 209 A
29 A 210 A
30 A 211 B
31 B 212 A
32 A 213 A
33 A 214 A
34 A 215 A
35 A 216 A
36 B 217 B
37 A 218 B
38 A 219 A
39 B 220 B
40 A 221 B
41 B 222 B
42 B 223 A
43 B 224 A
44 A 225 A
45 B 226 A
46 B 227 A
47 B 228 A
48 B 229 A
49 B 230 A
50 A 231 B
51 A 232 B
52 A 233 B
53 A 234 A
54 B 235 A
55 A 236 A
56 B 237 A
57 B 238 A
58 B 239 A
59 B 240 A
60 A 241 A
61 A 242 A
62 A 243 A
63 B 244 A
64 A 245 A
65 A 246 A
66 A 247 A
67 A 248 A
68 B 249 A
69 B 250 A
70 A 251 A
71 A 252 A
72 A 253 A
73 A 254 B
74 A 255 A
75 A 256 A
76 A 257 A
77 C 258 A
78 A 259 A
79 A 260 A
80 B 261 A
81 A 262 A
82 B 263 A
83 B 264 B
84 A 265 A
85 A 266 A
86 A 267 A
87 B 268 A
88 A 269 A
89 B 270 A
90 A 271 A
91 A 272 B
92 A 273 A
93 A 274 A
94 A 275 A
95 A 276 A
96 A 277 B
97 A 278 A
98 B 279 A
99 A 280 B
100 A 281 A
101 A 282 A
102 A 283 A
103 A 284 A
104 A 285 A
105 A 286 A
106 A 287 A
107 A 288 A
108 A 289 B
109 A 290 A
110 A 291 A
111 A 292 A
112 A 293 B
113 A 294 B
114 A 295 A
115 A 296 A
116 A 297 A
117 B 298 A
118 A 299 A
119 A 300 A
120 A 301 A
121 A 302 A
122 A 303 A
123 A 304 A
124 A 305 A
125 A 306 A
126 A 307 A
127 A 308 A
128 A 309 A
129 A 310 A
130 A 311 A
131 A 312 A
132 A 313 A
133 A 314 A
134 A 315 A
135 A 316 A
136 A 317 A
137 A 318 A
138 A 319 A
139 A 320 A
140 A 321 A
141 A 322 A
142 B 323 A
143 A 324 A
144 A 325 A
145 A 326 A
146 A 327 A
147 A 328 A
148 A 329 A
149 A 330 A
150 A 331 A
151 A 332 A
152 A 333 A
153 A 334 A
154 A 335 A
155 A 336 B
156 A 337 C
157 A 338 C
158 A 339 C
159 B 340 C
160 A 341 C
161 A 342 C
162 B 343 B
163 A 344 C
164 A 345 B
165 A 346 B
166 A 347 C
167 B 348 C
168 A 349 B
169 A 350 B
170 B 351 B
171 A 352 B
172 A 353 C
173 A 354 C
174 A 355 A
175 A 356 B
176 A 357 B
177 A 358 B
178 A 359 B
179 A 360 B
180 A 361 B
181 B
All publications of quoting in this specification sheets and patent application are attached to herein in the mode of quoting as proof, as each single publication or patent application, are concrete and indicate and be introduced into as a reference individually.Although explanation and embodiment describe in detail foregoing invention by way of example for clear understanding, but under the condition of spirit or scope that does not deviate from accessory claim, can to it, carry out some change and modification in accordance with the teachings of the present invention, this is apparent to those of ordinary skills.

Claims (20)

1. the compound of formula (I):
Figure 2012800188626100001DEST_PATH_IMAGE002
Wherein
X is N or CR 1;
Y is N or CR 2;
Z is O, S or NH;
R 1h or C 1-6-alkyl;
R 2h or C 1-6-alkyl;
R 3c 1-8-alkyl, C 2-8-thiazolinyl, C 3-8-cycloalkyl, aryl, or heteroaryl, wherein, (a) C 1-8-alkyl or C 2-8-thiazolinyl is optionally selected from following substituting group and replaces by one or more: halogen, cyano group, nitro ,-OR a,-C (O) R a,-C (O) OR a,-OC (O) R a,-NR br c,-NR bc (O) R a,-NHC (O) NHR b,-C (O) NR br c,-NHSO 2r awith-SO 2nR bnR c; (b) C 3-8-cycloalkyl, aryl and heteroaryl are optionally selected from following substituting group and replace by one or more: C 1-6-alkyl, C 1-6-haloalkyl, C 2-6-thiazolinyl, Heterocyclylalkyl, aryl, heteroaryl, halogen, oxo, cyano group, nitro ,-OR d,-C (O) R d,-C (O) OR d,-OC (O) R d,-SR d,-S (O) R d,-SO 2r d,-NR er f,-NHC (O) R e,-NHC (O) NHR e,-NHC (O) OR e,-NHSO 2r d,-C (O) NHR ewith-SO 2nHNR e;
R 4be
(a) phenyl, naphthyl, tetralyl, indenyl or indanyl, wherein phenyl, naphthyl, tetralyl, indenyl or indanyl are optionally by one or more R 5replace; Or
(b) 5-16 unit monocycle, dicyclo or tricyclic heterocyclic base, wherein heterocyclic radical is optionally by one or more R 6replace;
R 5when occurring, be CN independently at every turn, NO 2, halogen, C 1-6-alkyl, OR g, SR g, C (O) R g, C (O) NR hr i, C (O) OR g, NR hr i, NR hc (O) R g, S (O) 2r g, NR hs (O) 2r g, S (O) 2nR hr i, aryl, cycloalkyl, heteroaryl, Heterocyclylalkyl or heterocycloalkenyl, wherein C 1-6-alkyl is optionally selected from following substituting group and replaces by one or more: CN, halogen, hydroxyl, S (O) 2nH (C 1-6-alkyl), C 1-6-alkoxyl group, Heterocyclylalkyl, cycloalkyl, heteroaryl, aryl ,-NH 2,-NHC 1-6-alkyl and-N (C 1-6-alkyl) 2; Wherein aryl, cycloalkyl, heteroaryl or Heterocyclylalkyl, separately or as the part of another part, optionally by one or more R 7replace;
R 6when occurring, be CN independently at every turn, NO 2, halogen, C 3-8cycloalkyl, OR j, SR j, C (O) R j, C (O) NR kr l, C (O) OR j, NR kr l, NR kc (O) R j, S (O) 2r j, NR ks (O) 2r jor S (O) 2nR kr l, C wherein 1-6-alkyl is optionally selected from following substituting group and replaces by one or more: CN, halogen, hydroxyl, C 1-6-alkoxyl group, Heterocyclylalkyl, cycloalkyl, heteroaryl, aryl ,-NH 2,-NHC 1-6-alkyl and-N (C 1-6-alkyl) 2; Wherein Heterocyclylalkyl, cycloalkyl, heteroaryl, aryl, separately or as the part of another part, optionally by one, two or three replace independently selected from following substituting group: CN, halogen, heteroaryl, benzyl and C 1-6alkyl;
R 7when occurring, be CN independently at every turn, NO 2, halogen, oxo, C 1-6alkyl, aryl, C 3-8cycloalkyl, heteroaryl, Heterocyclylalkyl, OR m, SR m, C (O) R m, C (O) NR nr o, C (O) OR m, OC (O) R m, OC (O) NR nr o, NR nr o, NR nc (O) R m, S (O) R m, S (O) NR nr o, S (O) 2r m, NR ns (O) 2r mor S (O) 2nR nr o, C wherein 1-6-alkyl is optionally selected from following substituting group and replaces by one or more: CN, halogen, hydroxyl, C 1-6-alkoxyl group, Heterocyclylalkyl, cycloalkyl, aryl, heteroaryl ,-NH 2,-NHC 1-6-alkyl and-N (C 1-6-alkyl) 2, wherein aryl, C 3-8cycloalkyl, heteroaryl and Heterocyclylalkyl, separately or as the part of another part, optionally by one, two or three replace independently selected from following substituting group: CN, halogen and C 1-6alkyl;
R awhen occurring at every turn independently selected from H, C 1-6alkyl, C 1-6haloalkyl, aryl, C 3-8cycloalkyl, heteroaryl and Heterocyclylalkyl;
R band R cwhen occurring at every turn independently selected from H, C 1-6alkyl, C 1-6haloalkyl, aryl, C 3-8cycloalkyl, heteroaryl and Heterocyclylalkyl;
R dwhen occurring at every turn independently selected from H, C 1-6alkyl, C 1-6haloalkyl, aryl, C 3-8cycloalkyl, heteroaryl and Heterocyclylalkyl;
R eand R fwhen occurring at every turn independently selected from H, C 1-6alkyl, C 1-6haloalkyl, aryl, C 3-8cycloalkyl, heteroaryl and Heterocyclylalkyl;
R gwhen occurring at every turn independently selected from H, C 1-6alkyl, aryl, C 3-8cycloalkyl, heteroaryl and Heterocyclylalkyl; C wherein 1-6-alkyl is optionally selected from following substituting group and replaces by one or more: CN, halogen, hydroxyl, C 1-6-alkoxyl group, Heterocyclylalkyl ,-NH 2,-NHC 1-6-alkyl and-N (C 1-6-alkyl) 2, wherein aryl, C 3-8cycloalkyl, heteroaryl or Heterocyclylalkyl, separately or as the part of another part, be optionally selected from following substituting group and replace by one or more: halogen, C 1-6-alkyl, C 1-6-haloalkyl, C 1-6-hydroxyalkyl, hydroxyl, oxo, C 1-6-alkoxyl group, C 1-6-halogenated alkoxy ,-C (O) C 1-6-alkyl ,-S (O) 2c 1-6-alkyl ,-NH 2,-NH (C 1-6-alkyl) ,-N (C 1-6-alkyl) 2with-N (C 1-6-alkyl) (C 3-8-cycloalkyl);
R hand R iwhen occurring at every turn independently selected from H, C 1-6alkyl, aryl, C 3-8cycloalkyl, heteroaryl and Heterocyclylalkyl; C wherein 1-6-alkyl is optionally selected from following substituting group and replaces by one or more: CN, halogen, hydroxyl, C 1-6-alkoxyl group, Heterocyclylalkyl ,-NH 2,-NHC 1-6-alkyl and-N (C 1-6-alkyl) 2, wherein aryl, C 3-8cycloalkyl, heteroaryl or Heterocyclylalkyl, separately or as the part of another part, be optionally selected from following substituting group and replace by one or more: halogen, C 1-6-alkyl, C 1-6-haloalkyl, C 1-6-hydroxyalkyl, hydroxyl, oxo, C 1-6-alkoxyl group, C 1-6-halogenated alkoxy ,-C (O) C 1-6-alkyl ,-S (O) 2c 1-6-alkyl ,-NH 2,-NH (C 1-6-alkyl) ,-N (C 1-6-alkyl) 2with-N (C 1-6-alkyl) (C 3-8-cycloalkyl);
R jwhen occurring at every turn independently selected from H, C 1-6alkyl, aryl, C 3-8cycloalkyl, heteroaryl and Heterocyclylalkyl; C wherein 1-6-alkyl is optionally selected from following substituting group and replaces by one or more: halogen, hydroxyl, C 1-6-alkoxyl group ,-NH 2,-NHC 1-6-alkyl and-N (C 1-6-alkyl) 2, wherein aryl, C 3-8cycloalkyl, heteroaryl or Heterocyclylalkyl are optionally selected from following substituting group and replace by one or more: halogen, C 1-6-alkyl, C 1-6-haloalkyl, C 1-6-hydroxyalkyl, hydroxyl, oxo, C 1-6-alkoxyl group, C 1-6-halogenated alkoxy ,-NH 2,-NH (C 1-6-alkyl) and N (C 1-6-alkyl) 2;
R kand R lwhen occurring at every turn independently selected from H, C 1-6alkyl, aryl, C 3-8cycloalkyl, heteroaryl and Heterocyclylalkyl; C wherein 1-6-alkyl is optionally selected from following substituting group and replaces by one or more: halogen, hydroxyl, C 1-6-alkoxyl group ,-NH 2,-NHC 1-6-alkyl and-N (C 1-6-alkyl) 2, wherein aryl, C 3-8cycloalkyl, heteroaryl or Heterocyclylalkyl are optionally selected from following substituting group and replace by one or more: halogen, C 1-6-alkyl, C 1-6-haloalkyl, C 1-6-hydroxyalkyl, hydroxyl, oxo, C 1-6-alkoxyl group, C 1-6-halogenated alkoxy ,-NH 2,-NH (C 1-6-alkyl) and N (C 1-6-alkyl) 2;
R mwhen occurring at every turn independently selected from H, C 1-6alkyl, aryl, C 3-8cycloalkyl, heteroaryl and Heterocyclylalkyl; C wherein 1-6-alkyl is optionally selected from following substituting group and replaces by one or more: halogen, hydroxyl, C 1-6-alkoxyl group ,-NH 2,-NHC 1-6-alkyl and-N (C 1-6-alkyl) 2, wherein aryl, C 3-8cycloalkyl, heteroaryl or Heterocyclylalkyl are optionally selected from following substituting group and replace by one or more: halogen, C 1-6-alkyl, C 1-6-haloalkyl, C 1-6-hydroxyalkyl, hydroxyl, oxo, C 1-6-alkoxyl group, C 1-6-halogenated alkoxy ,-NH 2,-NH (C 1-6-alkyl) and N (C 1-6-alkyl) 2;
R nand R owhen occurring at every turn independently selected from H, C 1-6alkyl, aryl, C 3-8cycloalkyl, heteroaryl and Heterocyclylalkyl; C wherein 1-6-alkyl is optionally selected from following substituting group and replaces by one or more: halogen, hydroxyl, C 1-6-alkoxyl group ,-NH 2,-NHC 1-6-alkyl and-N (C 1-6-alkyl) 2, wherein aryl, C 3-8cycloalkyl, heteroaryl or Heterocyclylalkyl are optionally selected from following substituting group and replace by one or more: halogen, C 1-6-alkyl, C 1-6-haloalkyl, C 1-6-hydroxyalkyl, hydroxyl, oxo, C 1-6-alkoxyl group, C 1-6-halogenated alkoxy ,-NH 2,-NH (C 1-6-alkyl) and N (C 1-6-alkyl) 2;
Or its pharmacologically acceptable salt or solvate;
Condition is that described compound is not 6-(2,6-3,5-dimethylphenyl)-2-((4-(4-methyl isophthalic acid-piperazinyl) phenyl) amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one.
2. the compound of the formula of claim 1 (I), wherein X is CR 1, Y is CR 2.
3. the compound of the formula of claim 1 (I), wherein X is N, Y is CR 2.
4. the compound of the formula of claim 1 (I), wherein X is N, Y is N.
5. the compound of the formula of claim 1-4 any one (I), wherein Z is O.
6. the compound of the formula of claim 1-5 any one (I), wherein R 3c 1-8alkyl or C 2-8thiazolinyl.
7. the compound of the formula of claim 1-5 any one (I), wherein R 3c 3-8cycloalkyl.
8. the compound of the formula of claim 1-5 any one (I), wherein R 3be aryl, wherein aryl is selected from phenyl, naphthyl, indenyl, indanyl and tetralyl.
9. the compound of claim 8, wherein R 3be phenyl, wherein phenyl is optionally selected from following substituting group by one or two and replaces: halogen, C 1-6alkyl, C 1-6haloalkyl ,-OC 1-6alkyl and-OC 1-6haloalkyl.
10. the compound of the formula of claim 1-9 any one (I), wherein R 4it is phenyl.
The compound of 11. claims 10, wherein
R 4be phenyl, wherein phenyl is by Heterocyclylalkyl and optional one or two R 5replace, wherein R 5halogen, C 1-6alkyl, C 1-6haloalkyl or OR g, wherein Heterocyclylalkyl is optionally by one, two or three R 7replace; R wherein 7cN, NO 2, halogen, oxo, C 1-6alkyl, aryl, C 3-8cycloalkyl, heteroaryl, Heterocyclylalkyl, OR m, SR m, C (O) R m, C (O) NR nr o, C (O) OR m, OC (O) R m, OC (O) NR nr o, NR nr o, NR nc (O) R m, S (O) R m, S (O) NR nr o, S (O) 2r m, NR ns (O) 2r mor S (O) 2nR nr o, C wherein 1-6-alkyl is optionally selected from following substituting group and replaces by one or more: CN, halogen, hydroxyl, C 1-6-alkoxyl group, Heterocyclylalkyl, cycloalkyl, aryl, heteroaryl ,-NH 2,-NHC 1-6-alkyl and-N (C 1-6-alkyl) 2, wherein aryl, C 3-8cycloalkyl, heteroaryl and Heterocyclylalkyl, separately or as the part of another part, optionally by one, two or three replace independently selected from following substituting group: CN, halogen and C 1-6alkyl.
The compound of 12. claims 11, wherein
R 3be phenyl, wherein phenyl is selected from following substituting group by one or two and replaces: C 1-6-alkyl, C 1-6-haloalkyl, halogen and-OR d;
R 4be ;
R 5halogen, C 1-6-alkyl, C 1-6haloalkyl or OR g; With
P is 0 or 1.
The compound of 13. claims 10, wherein R 4be
Figure 2012800188626100001DEST_PATH_IMAGE006
R wherein 5halogen, C 1-6alkyl or C 1-6haloalkyl, R gbe selected from H, C 1-6alkyl, aryl, C 3-8cycloalkyl, heteroaryl and Heterocyclylalkyl; C wherein 1-6-alkyl is optionally selected from following substituting group and replaces by one or more: CN, halogen, hydroxyl, C 1-6-alkoxyl group, Heterocyclylalkyl ,-NH 2,-NHC 1-6-alkyl and-N (C 1-6-alkyl) 2, wherein aryl, C 3-8cycloalkyl, heteroaryl or Heterocyclylalkyl, separately or as the part of another part, be optionally selected from following substituting group and replace by one or more: halogen, C 1-6-alkyl, C 1-6-haloalkyl, C 1-6-hydroxyalkyl, hydroxyl, oxo, C 1-6-alkoxyl group, C 1-6-halogenated alkoxy ,-C (O) C 1-6-alkyl ,-S (O) 2c 1-6-alkyl ,-NH 2,-NH (C 1-6-alkyl) ,-N (C 1-6-alkyl) 2with-N (C 1-6-alkyl) (C 3-8-cycloalkyl); R hand R iwhen occurring at every turn independently selected from H, C 1-6alkyl, aryl, C 3-8cycloalkyl, heteroaryl and Heterocyclylalkyl; C wherein 1-6-alkyl is optionally selected from following substituting group and replaces by one or more: CN, halogen, hydroxyl, C 1-6-alkoxyl group, Heterocyclylalkyl ,-NH 2,-NHC 1-6-alkyl and-N (C 1-6-alkyl) 2, wherein aryl, C 3-8cycloalkyl, heteroaryl or Heterocyclylalkyl, separately or as the part of another part, be optionally selected from following substituting group and replace by one or more: halogen, C 1-6-alkyl, C 1-6-haloalkyl, C 1-6-hydroxyalkyl, hydroxyl, oxo, C 1-6-alkoxyl group, C 1-6-halogenated alkoxy ,-C (O) C 1-6-alkyl ,-S (O) 2c 1-6-alkyl ,-NH 2,-NH (C 1-6-alkyl), N (C 1-6-alkyl) 2with-N (C 1-6-alkyl) (C 3-8-cycloalkyl); P is 0,1 or 2.
The compound of 14. claim 1-9 any one, wherein R 4naphthyl, tetralyl, indenyl or indanyl, wherein naphthyl, tetralyl, indenyl or indanyl are optionally by one or more R 5replace.
The compound of 15. claim 1-9 any one, wherein R 4be 7-11 unit bicyclic heterocyclic radical, wherein heterocyclic radical is optionally by one or more R 6replace.
The compound of 16. claim 1-9 any one, wherein R 4be 10-15 unit tricyclic heterocyclic base, wherein heterocyclic radical is optionally by one or more R 6replace.
The compound of 17. claims 1, is selected from:
6-(2-chloro-phenyl-)-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-anilino-6-(2-chloro-phenyl-) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(pyridin-4-yl is amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-[(2'-methyl-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(5,6,7,8-naphthane-2-base is amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[3-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-[(4-cyclohexyl phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(piperidin-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(pyrrolidin-1-yl methyl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(morpholine-4-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[3-(pyrrolidin-1-yl methyl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-[(1-ethanoyl-2,3-dihydro-1H-indoles-6-yl) amino]-6-(2-chloro-phenyl-) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-{[4-(4-ethanoyl piperazine-1-yl) phenyl] amino }-6-(2-chloro-phenyl-) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-aminomethyl phenyl)-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-{[4-(4-methylpiperazine-1-yl) phenyl] amino }-6-[2-(trifluoromethyl) phenyl] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-p-methoxy-phenyl)-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[2-methoxyl group-4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-[(1-methyl isophthalic acid, 2,3,4-tetrahydroquinoline-7-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
7-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino }-3,4-dihydro-isoquinoline-2 (1H)-formic acid tertiary butyl ester;
6-(2-chloro-phenyl-)-2-(1,2,3,4-tetrahydroisoquinoline-7-base is amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[3-methyl-4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-allyl group-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-cyclohexyl-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-9-methyl-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } Kui Linpyrimido quinoline [5,4-e] [1,2,4] triazolos [4,3-a] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-9-methyl-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } Kui Linpyrimido quinoline [5,4-e] [1,2,4] triazolos [4,3-a] pyrimidine-5 (6H)-one;
4-(2-chloro-phenyl-)-8-{[4-(4-methylpiperazine-1-yl) phenyl] amino } Kui Linpyrimido quinoline [5,4-e] tetrazolo [1,5-a] pyrimidine-5 (4H)-one;
6-(2-chloro-phenyl-)-2-(4-[4-(third-2-yl) piperazine-1-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(4-[4-(cyclohexyl methyl) piperazine-1-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
3-{[4-(4-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } phenyl) piperazine-1-yl] methyl } benzonitrile;
The chloro-4-of 2-{[3-(4-methylpiperazine-1-yl) phenyl] amino }-6-(2-chloro-phenyl-) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(the fluoro-4-[4-of 3-(third-2-yl) piperazine-1-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-[(2-methyl isophthalic acid, 2,3,4-tetrahydroisoquinoline-7-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(4-[2-(dimethylamino) oxyethyl group] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(4-[2-(morpholine-4-yl) oxyethyl group] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[3-methyl-4-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(1-methyl piperidine-4-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-{[4-(4-methylpiperazine-1-yl) phenyl] amino }-6-phenylimidazole [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one also;
6-(the chloro-4-aminomethyl phenyl of 2-)-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
4-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino }-N-phenylcyclohexane methane amide;
6-(2-chloro-phenyl-)-2-(4-[(4-methylpiperazine-1-yl) and carbonyl] phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(1H-pyrazoles-4-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(4-[2-(diethylamino) oxyethyl group] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(pyridin-3-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
4-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino }-N-(trans-4-hydroxy-cyclohexyl) benzamide;
4-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino }-N-ethyl benzamide;
6-(2-chloro-phenyl-)-2-(4-[(4-hydroxy piperidine-1-yl) and carbonyl] phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
4-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino }-N-(pyridin-4-yl) benzamide;
6-(2-chloro-phenyl-)-2-(4-[3-(diethylamino) propoxy-] and-3-fluorophenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(the fluoro-4-[2-of 3-(4-methylpiperazine-1-yl) oxyethyl group] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[2-(2-methoxy ethyl)-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-[(2,4,4-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-7-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(3-hydroxy-2-methyl phenyl)-2-(phenyl amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-[(4-aminophenyl) amino]-6-(2-chloro-phenyl-) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
N-(4-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } phenyl) ethanamide;
N-(4-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } phenyl) cyclopentane formamide;
N-(4-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } phenyl)-4-hydroxyl cyclohexane carboxamide;
N-(4-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } phenyl)-1-methyl piperidine-4-methane amide;
N-(4-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } phenyl) pyridine-4-methane amide;
6-(2,6-3,5-dimethylphenyl)-2-[(2'-methyl-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-(4-[4-(3-chlorobenzyl) piperazine-1-yl] and phenyl } amino)-6-(2-chloro-phenyl-) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(4-[4-(2-methoxy ethyl) piperazine-1-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[3-methoxyl group-4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(3-methoxyl group-4-[4-(third-2-yl) piperazine-1-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(3-methoxyl group-4-[2-(4-methylpiperazine-1-yl) oxyethyl group] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(3-hydroxy phenyl)-2-(phenyl amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-[(4-aminomethyl phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(piperidin-2-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(pyrrolidin-2-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(pyrrolidin-3-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-[(2'-methyl-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[3-methyl-4-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(piperazine-1-yl)-3-(trifluoromethyl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(4-[(2S) and-pyrrolidin-2-yl methoxyl group] phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(2-methyl-4-[3-(4-methylpiperazine-1-yl) propoxy-] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(morpholine-4-ylmethyl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(1H-imidazoles-1-ylmethyl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(1H-imidazoles-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[6-(piperazine-1-yl) pyridin-3-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(3-[3-(4-methylpiperazine-1-yl) propoxy-] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(3-[3-(piperidin-1-yl) propoxy-] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-(phenyl amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(3-methoxyl group-4-[2-(third-2-base is amino) oxyethyl group] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(the chloro-4-[2-of 3-(third-2-base is amino) oxyethyl group] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(methylol) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(1H-pyrazol-1-yl methyl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(1H-pyrazol-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-base amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-[(2'-ethanoyl-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl) amino]-6-(2-chloro-phenyl-) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-[(1-methyl isophthalic acid, 2,3,4-tetrahydroquinoline-6-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(1-[2-(dimethylamino) ethyl] and-2,3-dihydro-1H-indoles-5-yl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[2-(dimethylamino)-2,3-dihydro-1H-indenes-5-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-{[3-methyl-4-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-[(2,4,4-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-7-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-difluorophenyl)-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[2-(2-hydroxyethyl)-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[3-(methylol)-4-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(hexahydropyrrolo is [1,2-a] pyrazine-2 (1H)-yl also) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-[(4-hydroxy-3-methyl phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(4-[3-(diethylamino) propoxy-] and-3-aminomethyl phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[3-methyl-4-(piperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(Isosorbide-5-Nitrae-Diazesuberane-1-yl)-3-aminomethyl phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(2,3,4,5-tetrahydrochysene-1H-2-benzo-aza
Figure 2012800188626100001DEST_PATH_IMAGE008
-7-base is amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-[(3-methyl-2,3,4,5-tetrahydrochysene-1H-3-benzo-aza
Figure DEST_PATH_IMAGE008A
-7-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-[(1,1,2-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-7-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-(2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-base amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[3-methyl-4-(piperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-(1,2,3,4-tetrahydroisoquinoline-7-base is amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[3-ethyl-4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[2-(cyclohexyl methyl)-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[2-(dimethylamino)-2,3-dihydro-1H-indenes-5-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-(4-[4-(third-2-yl) piperazine-1-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[4-(hexahydropyrrolo is [1,2-a] pyrazine-2 (1H)-yl also) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[2-(2-ethyl-butyl)-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-(4-[2-(4-methylpiperazine-1-yl) ethyl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-(1-[2-(dimethylamino) ethyl] and-2,3-dihydro-1H-indoles-5-yl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[3-ethyl-4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[3-(methylol)-4-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-(1,2,3,4-tetrahydroisoquinoline-6-base is amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-4-fluorophenyl of 2,6-bis-)-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-4-fluorophenyl of 2,6-bis-)-2-{[3-methyl-4-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-4-fluorophenyl of 2,6-bis-)-2-[(2'-methyl-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-4-fluorophenyl of 2,6-bis-)-2-{[2-(dimethylamino)-2,3-dihydro-1H-indenes-5-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-(4-[(4-methylpiperazine-1-yl) and methyl] phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-(4-[(3R, 5S) and-3,5-lupetazin-1-yl]-3-fluorophenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[3, the fluoro-4-of 5-bis-(piperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[2-(cyclopropyl methyl)-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4,4-dimethyl-2-(pyridin-3-yl methyl)-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4,4-dimethyl-2-(thiene-3-yl-methyl)-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-[(1,1,2-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-6-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[4-(pyrrolidin-2-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[4-(piperidin-2-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
The chloro-4-of 2-{[3-(4-methylpiperazine-1-yl) phenyl] amino }-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-(3-methoxyl group-4-[4-(third-2-yl) piperazine-1-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(4-hydroxy piperidine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-{[2-(dimethylamino)-2,3-dihydro-1H-indenes-5-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-[(2'-methyl-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-{[4-(Isosorbide-5-Nitrae-Diazesuberane-1-yl)-3-aminomethyl phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-[(2'-methyl-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl) amino]-6-(third-2-yl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[4-(3-oxo piperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4,4-dimethyl-2-(third-2-yl)-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4,4-dimethyl-2-(4,4,4-trifluoro butyl)-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-[(1,1,2-trimethylammonium-2,3-dihydro-1H-isoindole-5-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-[(1,1,2,3,3-pentamethyl--2,3-dihydro-1H-isoindole-5-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[3-methoxyl group-4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-(4-[3-(diethylamino) propoxy-] and-3-fluorophenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-[(1,1,2-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-6-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-(4-[(1S, 4S) and-2,5-diazabicyclo [2.2.1] heptan-2-yl] phenyl } amino)-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-[(2,4,4-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-7-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[4-(4,4-difluoro piperidin-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[4-(3,3-difluoro piperidin-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-(the fluoro-4-[4-of 3-(third-2-yl) piperazine-1-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[4-(piperazine-1-yl)-3-(trifluoromethyl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(4-methylpiperazine-1-yl)-3-(third-2-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-{[4-(4-ethanoyl piperazine-1-yl) phenyl] amino }-6-(the chloro-6-fluorophenyl of 2-) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-[(4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-4-fluorophenyl of 2,6-bis-)-2-(2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-base amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-[(2-ethyl-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4,4-dimethyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(2-[4-(1H-imidazoles-1-yl) benzyl] and-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-(2-[(1-benzyl piepridine-4-yl) and methyl]-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl } amino)-6-(2-chloro-phenyl-) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-[(2'-ethanoyl-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl) amino]-6-(the chloro-4-fluorophenyl of 2,6-bis-) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[4-(4-hydroxy piperidine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-[(4-cyclohexyl phenyl) amino]-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[4-(pyrrolidin-3-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[4-(morpholine-4-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[4,4-dimethyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-{[2'-(cyclopropyl carbonyl)-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl] amino-6-(the chloro-4-fluorophenyl of 2,6-bis-) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-4-fluorophenyl of 2,6-bis-)-2-{[2'-(methylsulfonyl)-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl] amino imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-4-fluorophenyl of 2,6-bis-)-2-{[6-(piperazine-1-yl) pyridin-3-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[4-(2-oxo piperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-(4-[(1R, 4R) and-2,5-diazabicyclo [2.2.1] heptan-2-yl] phenyl } amino)-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[4-(4-methylpiperazine-1-yl)-3-(third-2-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-[(1,1,2,3,3-pentamethyl--2,3-dihydro-1H-isoindole-5-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-[(1,1,2-trimethylammonium-2,3-dihydro-1H-isoindole-5-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
(3aS, 10aS)-8-{[6-(2,6-dichlorophenyl)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino }-2,3,3a, 5,10,10a-hexahydropyrrolo is [3,4-c] [1] benzo-aza also
Figure DEST_PATH_IMAGE008AA
-4 (1H)-one;
6-(2,6-dichlorophenyl)-2-{[4-(6-oxo-Isosorbide-5-Nitrae, 5,6-tetrahydro pyridazine-3-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-(1,2,3-diazosulfide-5-base is amino)-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-(1,3-benzothiazol-6-yl is amino)-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-(4-[bis-(2-methoxy ethyl) amino] and phenyl } amino)-6-(2-chloro-phenyl-) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-[(3-cyclopropyl-2,3,4,5-tetrahydrochysene-1H-3-benzo-aza
Figure DEST_PATH_IMAGE008AAA
-7-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[3-(2,2-, bis-fluoro ethyls)-2,3,4,5-tetrahydrochysene-1H-3-benzo-aza
Figure DEST_PATH_IMAGE008AAAA
-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-4,6-difluorophenyl)-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-4,6-difluorophenyl)-2-[(2,4,4-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-7-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-4,6-difluorophenyl)-2-{[2-(dimethylamino)-2,3-dihydro-1H-indenes-5-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-[(4-{[3-(morpholine-4-yl) propyl group] amino } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(4-[4-(pyrrolidin-1-yl) piperidin-1-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(4-[4-(dimethylamino) piperidin-1-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-[(4-{[2-(1-methylpyrrolidin-2-yl) ethyl] amino } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
4-{[6-(2,6-dichlorophenyl)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } phenylformic acid 4-(dimethylamino) cyclohexyl ester;
6-(2,6-dichlorophenyl)-2-(1H-indazole-5-base is amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-(4-[(3S) and-3-(third-2-yl) piperazine-1-yl] phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-[(4-{1-[1-(dimethylamino)-3-methyl butyl] cyclobutyl } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-(4-[4-methyl-2-(methylamino)-1,3-thiazoles-5-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[6-(piperazine-1-yl) pyridin-3-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-(1H-indazole-6-base is amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
4-{[6-(2,6-dichlorophenyl)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } phenylformic acid (1R)-octahydro-2H-quinolizine-1-base ester;
4-{[6-(2,6-dichlorophenyl)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } phenylformic acid 2-[cyclopropyl (methyl) amino] ethyl ester;
6-(2,6-dichlorophenyl)-2-[(4-{[(1R, 5S)-7-ethyl-3,7-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-3-yl] carbonyl } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[3, the fluoro-4-of 5-bis-(piperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-({ 4-[(8aR)-hexahydropyrrolo is [1,2-a] pyrazine-2 (1H)-yl also] phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-(2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-base amino)-6-(4-hydroxy phenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[2'-(methylsulfonyl)-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl] amino imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-[(2'-ethanoyl-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl) amino]-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(octahydro-2H-pyrido [1,2-a] pyrazine-2-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-[(1,1,2-trimethylammonium-2,3-dihydro-1H-isoindole-5-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-[(1,1,2,3,3-pentamethyl--2,3-dihydro-1H-isoindole-5-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(4-[4-(trimethylene oxide-3-yl) piperazine-1-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-4-fluorophenyl of 2,6-bis-)-2-[(2,4,4-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-7-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-[(4-oxo-Isosorbide-5-Nitrae-dihydro cinnolines-6-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-{[4-(4-ethanoyl piperazine-1-yl) phenyl] amino }-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-(4-[4-(dimethylamino) piperidin-1-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
4-{[6-(2,6-dichlorophenyl)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } methyl benzoate;
6-(2-chloro-phenyl-)-2-{[3, the chloro-4-of 5-bis-(piperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(imidazo [1,2-a] pyridine-2-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(4-[4-oxo-3-(third-2-yl)-1,3-thiazoles alkane-2-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(2,3-glyoxalidine is [2,1-b] [1,3] thiazole-6-yl also) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(5-methyl-4-oxo-1,3-thiazoles alkane-2-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(imidazo [2,1-b] [1,3] thiazole-6-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(3-oxo-2,3-dihydro-1H-indazole-7-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-{[2'-(2,2-, bis-fluoro ethyls)-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl] amino imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-{[2'-(2-fluoro ethyl)-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl] amino imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-{[2'-(2-fluoro ethyl)-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl] amino imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-{[2-(diethylamino)-2,3-dihydro-1H-indenes-5-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-{[2-(diethylamino)-2,3-dihydro-1H-indenes-5-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-{[2-(cyclopropylamino)-2,3-dihydro-1H-indenes-5-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-{[2-(cyclopropylamino)-2,3-dihydro-1H-indenes-5-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-(2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-base amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-{[4-(Isosorbide-5-Nitrae '-Lian piperidines-1'-yl) phenyl] amino-6-(2-chloro-phenyl-) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(4-[(3R) and-3-(dimethylamino) pyrrolidin-1-yl] phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(4-[3-(trifluoromethyl) piperidin-1-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
3-[4-(4-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } phenyl) piperazine-1-yl] propionitrile;
3-[(4-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } phenyl) (cyclopropyl) amino] propionitrile;
6-(2-chloro-phenyl-)-2-[(4-{[2-(dimethylamino) ethyl] amino } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
1-(4-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } phenyl) piperidines-4-methane amide;
6-(2-chloro-phenyl-)-2-(4-[4-(morpholine-4-yl) piperidin-1-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-[(4-{[4-(dimethylamino) piperidin-1-yl] carbonyl } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
4-{[6-(2,6-dichlorophenyl)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino }-N-[4-(dimethylamino) cyclohexyl] benzamide;
4-{[6-(2,6-dichlorophenyl)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino }-N-(1-methyl piperidine-4-yl) benzamide;
6-(2,6-dichlorophenyl)-2-(4-[4-(pyrrolidin-1-yl) piperidin-1-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-[(2'-ethanoyl-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl) amino]-6-(the chloro-6-fluorophenyl of 2-) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-{[2'-(cyclopropyl carbonyl)-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl] amino imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-{[2'-(methylsulfonyl)-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl] amino imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-({ 4-[(8aR)-hexahydropyrrolo is [1,2-a] pyrazine-2 (1H)-yl also] phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-(4-[(3R) and-1-azabicyclo [2.2.2] oct-3-yl amino] phenyl } amino)-6-(2-chloro-phenyl-) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-[(4-{[2-(pyrrolidin-1-yl) ethyl] amino } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(4-[4-(pyridine-2-yl) piperazine-1-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-[(4-{[2-(morpholine-4-yl) ethyl] amino } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(4-[(2S) and-2-(pyrrolidin-1-yl methyl) pyrrolidin-1-yl] phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-[(4-{4-[3-(dimethylamino) propyl group] piperazine-1-yl } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(4-[(2R) and-2-(methoxymethyl) pyrrolidin-1-yl] phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
1-(4-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } phenyl)-N, N-diethyl piperidines-3-methane amide;
6-(2-chloro-phenyl-)-2-[(4-{[3-(2-oxo-pyrrolidine-1-yl) propyl group] amino } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(4-[4-(4-fluorophenyl) piperazine-1-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-(4-[4-(dimethylamino) piperidin-1-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-(2-[(3S) and-3-fluoropyrrolidine-1-yl]-2,3-dihydro-1H-indenes-5-yl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-(2-[(3S) and-3-fluoropyrrolidine-1-yl]-2,3-dihydro-1H-indenes-5-yl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-(2-[(2-fluoro ethyl) and amino]-2,3-dihydro-1H-indenes-5-yl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-(2-[(2-fluoro ethyl) and amino]-2,3-dihydro-1H-indenes-5-yl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-{[2-(propyl group is amino)-2,3-dihydro-1H-indenes-5-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-{[2-(propyl group is amino)-2,3-dihydro-1H-indenes-5-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-{[2-(pyrrolidin-1-yl)-2,3-dihydro-1H-indenes-5-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-[(4-{4-[2-(dimethylamino) ethyl] piperazine-1-yl } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-[(4-{[3-(dimethylamino) propyl group] (methyl) amino } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-[(4-{[2-(dimethylamino) ethyl] (ethyl) amino } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-[(4-{[2-(dimethylamino) ethyl] (methyl) amino } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(4-[(2S) and-2-(methoxymethyl) pyrrolidin-1-yl] phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-{[2'-(2-methylpropionyl)-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl] amino imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-{[2'-(2,2-dimethyl propylene acyl group)-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl] amino imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-{[2'-(cyclopentylcarbonyl)-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl] amino imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-[(4-{[2-(1H-imidazol-4 yl) ethyl] amino } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-[(4-{[3-(1H-imidazoles-1-yl) propyl group] amino } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(thiomorpholine-4-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-[(4-{ third-2-base [2-(third-2-base is amino) ethyl] amino } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
1-(4-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } phenyl) piperidines-3-methane amide;
6-(2,6-dichlorophenyl)-2-[(4-{[2-(1-methylpyrrolidin-2-yl) ethyl] amino } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[2'-(2-methylpropionyl)-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl] amino imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-{[2'-(cyclopropyl carbonyl)-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl] amino-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[2'-(2,2-dimethyl propylene acyl group)-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl] amino imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-(5,6,7,8-tetrahydrochysene-1,6-naphthyridines-3-base is amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-3-hydroxyl phenyl)-2-(2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-base amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-(2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-base amino)-6-(4-hydroxy-2-methyl phenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-{[2-(2,2-, bis-fluoro ethyls)-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-{[2-(2-fluoro ethyl)-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-{[4-(Isosorbide-5-Nitrae '-Lian piperidines-1'-yl) phenyl] amino-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-(4-[(3R) and-3-(dimethylamino) pyrrolidin-1-yl] phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-[(4-{[2-(dimethylamino) ethyl] amino } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-{[2'-(cyclopropyl alkylsulfonyl)-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl] amino-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[2'-(third-2-base alkylsulfonyl)-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl] amino imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[4-(1-methyl piperidine-4-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-{[4-(2,7-diaza spiro [3.5] ninth of the ten Heavenly Stems-7-yl) phenyl] amino }-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(4-[2-(trifluoromethyl) pyrrolidin-1-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(piperidin-4-yl oxygen base) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(piperidin-4-ylmethyl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(hexahydropyrrolo is [3,4-c] pyrroles-2 (1H)-yl also) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
1-(4-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } phenyl)-N-methyl Toluidrin;
4-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino }-N, N-diethyl benzene sulfonamide;
2-{[2-(cyclopropylamino)-2,3-dihydro-1H-indenes-5-yl] amino }-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-(2-[(2-fluoro ethyl) and amino]-2,3-dihydro-1H-indenes-5-yl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[2-(propyl group is amino)-2,3-dihydro-1H-indenes-5-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-{[4-(2-ethanoyl-2,7-diaza spiro [3.5] ninth of the ten Heavenly Stems-7-yl) phenyl] amino }-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-(4-[2-(methylsulfonyl)-2,7-diaza spiro [3.5] ninth of the ten Heavenly Stems-7-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
7'-{[6-(the chloro-6-fluorophenyl of 2-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino }-N-methyl isophthalic acid ' H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-2'(3'H)-methane amide;
7'-{[6-(the chloro-6-fluorophenyl of 2-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino }-N-(third-2-yl)-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-2'(3'H)-methane amide;
6-(2,6-dichlorophenyl)-2-{[2-(2-fluoro ethyl)-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-(4-[6-(methylsulfonyl)-2,6-diaza spiro [3.3] heptan-2-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[2-(pyrrolidin-1-yl)-2,3-dihydro-1H-indenes-5-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-(2-[(3S) and-3-fluoropyrrolidine-1-yl]-2,3-dihydro-1H-indenes-5-yl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-[(4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[4-(piperidin-4-yl is amino) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-{[4-(1-methyl piperidine-4-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-[(2-ethanoyl-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl) amino]-6-(the chloro-6-fluorophenyl of 2-) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-{[2-(cyclopropyl carbonyl)-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-{[4,4-dimethyl-2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-{[4-(2,6-diaza spiro [3.4] pungent-2-yl) phenyl] amino }-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-{[4-(2,7-diaza spiro [3.5] ninth of the ten Heavenly Stems-2-yl) phenyl] amino }-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-(4-[(3S) and-3-(dimethylamino) pyrrolidin-1-yl] phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(the chloro-6-fluorophenyl of 2-)-2-{[2-(hydroxyacetyl)-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
7-{[6-(the chloro-6-fluorophenyl of 2-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino }-4,4-dimethyl-3,4-dihydro-isoquinoline-2 (1H)-sulphonamide;
2-[(2-ethanoyl-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl) amino]-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[4,4-dimethyl-2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[2-(ethylsulfonyl)-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-(4-[(1-ethanoyl piperidin-4-yl) and amino] phenyl } amino)-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-[(4-{[1-(methylsulfonyl) piperidin-4-yl] amino } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[4-(9-methyl-3,9-diaza spiro [5.5] 10 one-3-yls) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-(4-[6-(methylsulfonyl)-2, and 6-diaza spiro [3.4] is pungent-2-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-({ 4-[(8aS)-hexahydropyrrolo is [1,2-a] pyrazine-2 (1H)-yl also] phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-({ 4-[(3aR, 6aR)-5-methyl hexahydropyrrolo is [3,4-b] pyrroles-1 (2H)-yl also] phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-[(4-{[2-(dimethylamino) ethyl] (ethyl) amino } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-[(4-{ third-2-base [2-(third-2-base is amino) ethyl] amino } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-[(2-ethanoyl-1,2,3,4-tetrahydroisoquinoline-7-yl) amino]-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,6-dichlorophenyl)-2-{[2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-[(2-ethanoyl-1,2,3,4-tetrahydroisoquinoline-6-yl) amino]-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-thioketones;
6-(2-chloro-phenyl-)-5-imino--N-[4-(4-methylpiperazine-1-yl) phenyl]-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-amine also;
6-(2-chloro-phenyl-)-2-[(2,4,4-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-7-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-thioketones;
6-(2-chloro-phenyl-)-5-imino--N-(2,4,4-trimethylammonium-1,2,3,4-tetrahydroisoquinoline-7-yl)-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-amine also;
6-(3-fluorophenyl)-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(3-chloro-phenyl-)-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2,4-Dimethoxyphenyl)-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[5-(4-ethyl piperazidine-1-yl) pyridine-2-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
The chloro-4-of 6-[2-(trifluoromethyl) phenyl]-2-{[4-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-{[4-(4-methylpiperazine-1-yl) phenyl] amino }-6-[2-(trifluoromethoxy) phenyl] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
4-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino } phenylformic acid;
2-[(4-bromophenyl) amino]-6-(2-chloro-phenyl-) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(3-methoxyl group-2-aminomethyl phenyl)-2-(phenyl amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-{[4-(Isosorbide-5-Nitrae-Diazesuberane-1-yl)-3-aminomethyl phenyl] amino }-6-(2,6-dichlorophenyl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
2-{[4-(4-methylpiperazine-1-yl) phenyl] amino }-6-(third-2-yl) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[3, the fluoro-4-of 5-bis-(4-methylpiperazine-1-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(trifluoromethyl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(1,3-thiazoles-4-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(1,3-thiazoles-2-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-{[4-(1,8-naphthyridines-2-yl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(4-[(2S) and-2-(trifluoromethyl) pyrrolidin-1-yl] phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
The chloro-4-of 2-{[3-(4-methylpiperazine-1-yl)-5-(trifluoromethyl) phenyl] amino }-6-(2-chloro-phenyl-) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
The chloro-4-of 6-(2-chloro-phenyl-)-2-{[3-(piperazine-1-yl)-5-(trifluoromethyl) phenyl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-[(2'-methyl-2', 3'-dihydro-1'H-spiral shell [cyclopropane-Isosorbide-5-Nitrae '-isoquinoline 99.9]-7'-yl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-thioketones;
2-{[7-{[6-(2-chloro-phenyl-)-5-oxo-5,6-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-2-base also] amino }-4,4-dimethyl-3,4-dihydro-isoquinoline-2 (1H)-yl] methyl } benzonitrile;
6-(2-chloro-phenyl-)-2-{[4,4-dimethyl-2-(4-propoxy-benzyl)-1,2,3,4-tetrahydroisoquinoline-7-yl] amino } imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(the fluoro-5-of 2-[3-(trifluoromethyl) benzyl] and-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-[(4-{2-[(2R)-2-methylpyrrolidin-1-yl] ethyl } phenyl) amino] imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one;
6-(2-chloro-phenyl-)-2-(4-[2-(morpholine-4-yl)-1,3-thiazoles-4-yl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one; With
6-(2-chloro-phenyl-)-2-(4-[2-(6-toluquinoline-2-yl) ethyl] and phenyl } amino) imidazo [1,2-a] Kui Linpyrimido quinoline [5,4-e] pyrimidine-5 (6H)-one.
The pharmaceutical composition of 18. compounds that comprise claim 1-17 any one or pharmacologically acceptable salt and pharmaceutically acceptable vehicle.
The method of the mammiferous cancer of 19. treatment, the method comprises: the compound or the pharmacologically acceptable salt that give the claim 1-17 any one of its treatment acceptable amount.
20. reduce the method for mammiferous gross tumor volume, and the method comprises: the compound or the pharmacologically acceptable salt that give the claim 1-17 any one of its treatment acceptable amount.
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